Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005125 cytokine activity	IBA GO_REF:0000033	ACCEPT	Summary: DBL-1 functions as a secreted signaling molecule similar to cytokines, activating receptor-mediated signaling cascades. As a TGF-beta/BMP superfamily member, it acts as a paracrine signal from neurons to hypodermal cells. The IBA annotation is phylogenetically sound given DBL-1's membership in the TGF-beta superfamily. Reason: DBL-1 is a secreted signaling ligand that activates receptor-mediated pathways, consistent with cytokine activity. The IBA annotation correctly captures this molecular function based on phylogenetic inference from BMP family members. Supporting Evidence: PMID:9847238 DBL-1 acts as a dose-dependent regulator of these processes file:worm/dbl-1/dbl-1-deep-research-falcon.md model: Edison Scientific Literature
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: DBL-1 is a secreted protein that signals from neurons to hypodermal cells in a paracrine manner. As a TGF-beta/BMP family member, it is processed and secreted to act on target cells expressing cognate receptors. Reason: DBL-1 is established as a secreted ligand that acts non-cell-autonomously. UniProt annotation indicates "Secreted" subcellular location. The protein signals from neurons to the hypodermis, requiring extracellular localization for its function. Supporting Evidence: PMID:12397107 As dbl-1 is expressed primarily in the nervous system, these results suggest a model in which postembryonic growth of hypodermal cells is regulated by TGFbeta-related signaling from the nervous system to the hypodermis
GO:0030509 BMP signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: DBL-1 is the ligand of the C. elegans BMP-like (Sma/Mab) signaling pathway. This is a core function of the protein, established through extensive genetic and biochemical studies. Reason: DBL-1 is the founding member of the C. elegans BMP pathway. PMID:9847238 identified it as a BMP homolog, and subsequent studies confirmed it signals through SMA-6 receptor and SMAD proteins. This is the central molecular function of DBL-1. Supporting Evidence: PMID:9847238 We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes PMID:12717735 In the nematode Caenorhabditis elegans, a TGFbeta-related signaling pathway regulates body size and male tail morphogenesis
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation based on InterPro domain and UniProt subcellular location. DBL-1 is a secreted protein, so this annotation is correct but less specific than GO:0005615 (extracellular space) which is also annotated. Reason: As a secreted TGF-beta ligand, DBL-1 is correctly annotated to extracellular region. This is a broader term than extracellular space but accurately reflects the protein's localization after secretion. Supporting Evidence: PMID:9847238 A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans
GO:0008083 growth factor activity	IEA GO_REF:0000120	ACCEPT	Summary: DBL-1 acts as a dose-dependent regulator of body size, functioning as a growth factor. Loss-of-function causes reduced body size while overexpression causes increased body size. Reason: DBL-1 functions as a classical growth factor - it is a secreted signaling molecule that regulates cell and organism size in a dose-dependent manner. PMID:9847238 demonstrates both loss-of-function (small) and gain-of-function (large) body size phenotypes. Supporting Evidence: PMID:9847238 Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures
GO:0010628 positive regulation of gene expression	IMP PMID:18158917 Regulation of rnt-1 expression mediated by the opposing effe...	ACCEPT	Summary: PMID:18158917 shows DBL-1 is required for counteracting BRO-1-mediated repression of rnt-1 expression at postembryonic stages, and ectopic DBL-1 expression induces rnt-1 transcription. Reason: The publication demonstrates DBL-1 positively regulates rnt-1 gene expression, opposing the repressive activity of BRO-1. This is a well-characterized regulatory relationship where DBL-1/TGF-beta signaling activates downstream gene expression. Supporting Evidence: PMID:18158917 we found that the TGFbeta homolog, DBL-1, was required for counteracting the repressive activity of BRO-1 at postembryonic stages
GO:0019216 regulation of lipid metabolic process	IMP PMID:29162682 Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulatio...	ACCEPT	Summary: PMID:29162682 demonstrates DBL-1 regulates lipid accumulation in C. elegans. Both loss and gain of DBL-1 function result in reduced lipid stores. DBL-1 acts upstream of insulin/IGF-1 signaling in lipid metabolism. Reason: This is a well-established secondary function of DBL-1. The study shows dbl-1 mutants have reduction in neutral lipids, and demonstrates epistatic relationship with DAF-2/insulin signaling for lipid regulation. Supporting Evidence: PMID:29162682 Similarly, we observed a decrease in dbl-1 mutants by ∼35% compared to wild type PMID:29162682 genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism
GO:0022604 regulation of cell morphogenesis	IMP PMID:24690231 CEH-28 activates dbl-1 expression and TGF-β signaling in the...	ACCEPT	Summary: PMID:24690231 shows dbl-1 mutants exhibit morphological defects in g1 gland cells located adjacent to M4 neuron in the pharynx, and these defects can be partially rescued by M4-specific expression of dbl-1. Reason: The study demonstrates DBL-1 is required for proper gland cell morphology via an R-Smad-independent TGF-beta signaling mechanism. This represents a distinct morphogenetic function of DBL-1. Supporting Evidence: PMID:24690231 both ceh-28 and dbl-1 mutants exhibit morphological defects in the g1 gland cells located adjacent to M4 in the pharynx, and these defects can be partially rescued by M4-specific expression of dbl-1 in these mutants
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:19198592 Neuroimmune regulation of antimicrobial peptide expression b...	ACCEPT	Summary: PMID:19198592 demonstrates neuronal expression of DBL-1 promotes transcription of antimicrobial peptide genes (cnc-2 caenacin) in the epidermis in a dose-dependent paracrine manner. Reason: The study shows DBL-1 activates transcription of antimicrobial peptide genes in the epidermis. As TGF-beta signaling ultimately activates SMAD-mediated transcription, this annotation accurately reflects DBL-1's role in promoting gene expression. Supporting Evidence: PMID:19198592 neuronal expression of the transforming growth factor-beta homolog DBL-1 promoted cnc-2 expression in the epidermis in a dose-dependent paracrine way
GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway	IGI PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ...	MODIFY	Summary: PMID:28068334 demonstrates tetraspanins TSP-12 and TSP-14 promote BMP signaling through ADAM10/SUP-17, with genetic interactions involving dbl-1 pathway components. The IGI evidence reflects genetic interactions showing positive regulation of TGF-beta signaling. Reason: While the annotation captures DBL-1's role in promoting BMP signaling, DBL-1 itself IS the TGF-beta pathway ligand rather than a regulator of the pathway. The more accurate annotation would be "BMP signaling pathway" (GO:0030509) which is already annotated. This annotation is somewhat circular - DBL-1 doesn't regulate TGF-beta signaling, it IS the signal. Proposed replacements: BMP signaling pathway Supporting Evidence: PMID:28068334 Here, we show that TSP-12 and TSP-14 function redundantly in BMP signaling by regulating the cell surface localization of the ADAM10
GO:0042661 regulation of mesodermal cell fate specification	IGI PMID:25978409 Promotion of bone morphogenetic protein signaling by tetrasp...	KEEP AS NON CORE	Summary: PMID:25978409 describes the role of the Sma/Mab pathway (including DBL-1) in regulating the postembryonic M lineage mesoderm development. Mutations in Sma/Mab pathway components suppress sma-9 M lineage defects. Reason: While the Sma/Mab pathway involving DBL-1 does affect M lineage patterning, this is demonstrated primarily through suppression of sma-9 mutant phenotypes rather than direct regulation. The core function of DBL-1 is body size regulation and male tail patterning; M lineage effects are more peripheral. Supporting Evidence: PMID:25978409 We have shown that mutations in the core components of the Sma/Mab pathway (Fig 2A) do not cause any M lineage defect on their own, but they suppress the dorsoventral patterning defects of sma-9 mutants
GO:0010468 regulation of gene expression	IMP PMID:17526726 Specificity and complexity of the Caenorhabditis elegans inn...	ACCEPT	Summary: PMID:17526726 shows DBL-1 pathway regulates expression of distinct but overlapping sets of antimicrobial genes as part of the C. elegans innate immune response. Reason: DBL-1/TGF-beta signaling regulates gene expression as part of its mechanism of action. The study demonstrates immune pathway signaling by DBL-1 affects antimicrobial gene expression patterns. Supporting Evidence: PMID:17526726 we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes
GO:0050832 defense response to fungus	IMP PMID:19198592 Neuroimmune regulation of antimicrobial peptide expression b...	ACCEPT	Summary: PMID:19198592 demonstrates DBL-1 promotes antifungal defense by activating expression of caenacin antimicrobial peptides in the epidermis in response to Drechmeria coniospora fungal infection. Reason: This is a well-characterized immune function of DBL-1. The study shows neuronal DBL-1 activates epidermal antimicrobial peptide expression during fungal infection via a non-canonical TGF-beta pathway. Supporting Evidence: PMID:19198592 After being infected by the fungus Drechmeria coniospora, Caenorhabditis elegans produces antimicrobial peptides in its epidermis PMID:19198592 The caenacin (cnc) genes enhanced survival after fungal infection
GO:0050829 defense response to Gram-negative bacterium	IMP PMID:17975555 A conserved Toll-like receptor is required for Caenorhabditi...	ACCEPT	Summary: PMID:17975555 demonstrates the role of TOL-1 and associated pathways including DBL-1 in defense against Salmonella enterica (Gram-negative bacterium) infection. Reason: DBL-1 contributes to innate immune defense against bacterial pathogens. UniProt annotation indicates "Plays a protective role in response to infection by the Gram-negative bacterium S.marcescens, by activating expression of genes involved in innate immunity." Supporting Evidence: PMID:17975555 tol-1(nr2033) mutants are killed by the human pathogen Salmonella enterica
GO:0050830 defense response to Gram-positive bacterium	IMP PMID:17975555 A conserved Toll-like receptor is required for Caenorhabditi...	ACCEPT	Summary: The annotation suggests DBL-1 is involved in defense against Gram-positive bacteria based on PMID:17975555, though the paper primarily focuses on Gram-negative Salmonella. Reason: DBL-1 is part of the C. elegans innate immune response system. UniProt annotation indicates involvement in antibacterial defense. The broader innate immune role of DBL-1 signaling encompasses responses to both Gram-negative and Gram-positive bacteria. Supporting Evidence: PMID:17975555 The results indicate that TOL-1 has a direct role in defence response to certain Gram-negative bacteria
GO:0005615 extracellular space	ISS PMID:9847238 A BMP homolog acts as a dose-dependent regulator of body siz...	ACCEPT	Summary: ISS annotation based on similarity to BMP proteins which are secreted ligands. PMID:9847238 identified DBL-1 as a BMP homolog. Duplicate of the IBA annotation. Reason: This annotation is correct based on homology to secreted BMP ligands. DBL-1 signals from neurons to target cells, requiring extracellular localization. Keeping both ISS and IBA provides independent evidence support. Supporting Evidence: PMID:9847238 a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes
GO:0030509 BMP signaling pathway	ISS PMID:9847238 A BMP homolog acts as a dose-dependent regulator of body siz...	ACCEPT	Summary: ISS annotation based on sequence similarity to BMP ligands. PMID:9847238 established DBL-1 as a BMP homolog. Duplicate of IBA annotation. Reason: DBL-1 is the ligand of the C. elegans BMP (Sma/Mab) pathway. This is the core function of the protein, supported by both phylogenetic (IBA) and sequence similarity (ISS) evidence. Supporting Evidence: PMID:9847238 Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand
GO:0070700 BMP receptor binding	ISS PMID:9847238 A BMP homolog acts as a dose-dependent regulator of body siz...	ACCEPT	Summary: ISS annotation based on homology to BMP ligands that bind BMP receptors. DBL-1 signals through the SMA-6 type I receptor and DAF-4 type II receptor. Reason: As a BMP ligand, DBL-1 must bind to its cognate receptors (SMA-6 and DAF-4) to transduce signals. This molecular function is correctly inferred from homology to vertebrate BMPs that bind BMP receptors. Supporting Evidence: PMID:9847238 Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway PMID:11784045 One of these pathways regulates body length and is composed of the ligand DBL-1, serine/threonine protein kinase receptors SMA-6 and DAF-4
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:12571101 Cyclic GMP-dependent protein kinase EGL-4 controls body size...	ACCEPT	Summary: PMID:12571101 shows EGL-4/cGMP-dependent protein kinase represses body size through DBL-1/TGF-beta pathway. Genetic analysis places DBL-1 as a positive regulator of body growth. Reason: DBL-1 positively regulates body size - loss-of-function causes small body size and overexpression causes large body size. This is the primary phenotypic function of DBL-1. Supporting Evidence: PMID:12571101 Experiments on genetic interaction suggest that the cGMP-EGL-4 signaling pathway represses body size and lifespan through DBL-1/TGF-beta and insulin pathways, respectively
GO:0045087 innate immune response	IMP PMID:19198592 Neuroimmune regulation of antimicrobial peptide expression b...	ACCEPT	Summary: PMID:19198592 demonstrates DBL-1 functions in neuroimmune regulation, activating antimicrobial peptide expression in epidermis during pathogen infection. Reason: DBL-1 contributes to innate immunity by activating antimicrobial peptide genes via a noncanonical TGF-beta signaling pathway. This is a well-established secondary function of DBL-1. Supporting Evidence: PMID:19198592 antifungal defenses are coordinately regulated by a cell-autonomous p38 cascade and a distinct cytokine-like transforming growth factor-beta signal from the nervous system
GO:0032877 positive regulation of DNA endoreduplication	IMP PMID:12019225 Increased or decreased levels of Caenorhabditis elegans lon-...	ACCEPT	Summary: PMID:12019225 shows dbl-1 loss-of-function causes decreased hypodermal nuclear ploidy (endoreduplication) in hyp7 syncytial cells, indicating DBL-1 positively regulates this process. Reason: The study demonstrates that dbl-1 mutants have reduced ploidy in hypodermal nuclei, indicating DBL-1 promotes endoreduplication. This contributes to the body size phenotype. Supporting Evidence: PMID:12019225 loss-of-function mutations in dbl-1 and lon-1, respectively, cause a decrease or increase in the ploidy of nuclei in the hypodermal syncytial cell, hyp7
GO:0040018 positive regulation of multicellular organism growth	IGI PMID:12051826 lon-1 regulates Caenorhabditis elegans body size downstream ...	ACCEPT	Summary: PMID:12051826 demonstrates lon-1 is a downstream target of DBL-1 signaling that regulates body size. Genetic analysis shows lon-1 acts downstream of dbl-1 in the Sma/Mab pathway. Reason: Genetic interactions between dbl-1 and lon-1 confirm DBL-1's role in body size regulation. lon-1 mRNA is up-regulated when dbl-1 signaling is reduced, showing negative regulation by the pathway. Supporting Evidence: PMID:12051826 lon-1 regulates body size morphogenesis PMID:12051826 lon-1 lies downstream of the Sma/Mab signaling cascade
GO:0040018 positive regulation of multicellular organism growth	IGI PMID:17240342 Glypican LON-2 is a conserved negative regulator of BMP-like...	ACCEPT	Summary: PMID:17240342 shows LON-2 glypican negatively regulates BMP-like signaling by potentially binding to DBL-1 and attenuating ligand-receptor interactions. Reason: Genetic analysis places lon-2 upstream of dbl-1 as a negative regulator. The interaction between LON-2 and DBL-1 confirms DBL-1's role in promoting growth. Supporting Evidence: PMID:17240342 LON-2 negatively regulates a BMP-like signaling pathway that controls body length in C. elegans PMID:17240342 lon-2 acts genetically upstream of the BMP-like gene dbl-1
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:12397107 The expression of TGFbeta signal transducers in the hypoderm...	ACCEPT	Summary: PMID:12397107 demonstrates dbl-1 loss-of-function causes reduced body size due to decreased postembryonic growth, with hypodermal blast cell size most affected. Reason: This study provides detailed characterization of body size regulation by DBL-1, showing the signaling pathway acts in hypodermis to regulate growth. Supporting Evidence: PMID:12397107 Loss of function of the signaling ligand (dbl-1), receptors (daf-4 and sma-6) or Smads (sma-2, sma-3 and sma-4) results in viable, but smaller animals because of a reduction in postembryonic growth
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:12717735 Genetic screen for small body size mutants in C. elegans rev...	ACCEPT	Summary: PMID:12717735 identifies dbl-1 mutations in a genetic screen for small body size mutants, confirming its role in growth regulation. Reason: Forward genetic screen confirms dbl-1 as a key regulator of body size within the TGF-beta pathway. Supporting Evidence: PMID:12717735 Among 34 Small mutants, many mutations disrupt genes encoding recognizable components of the TGFbeta pathway: DBL-1 ligand
GO:0045138 nematode male tail tip morphogenesis	IMP PMID:12717735 Genetic screen for small body size mutants in C. elegans rev...	ACCEPT	Summary: PMID:12717735 shows dbl-1 mutants have male tail morphogenesis defects including ray fusions and abnormal spicules. Reason: Male tail patterning is a core function of DBL-1, affecting sensory ray formation and mating structures. This is one of the two primary phenotypes (along with body size) of the Sma/Mab pathway. Supporting Evidence: PMID:9847238 Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures PMID:12717735 Four of these 11 genes, sma-9, sma-14, sma-16, and sma-20 affect male tail morphogenesis as well as body size
GO:0002119 nematode larval development	IMP PMID:12397107 The expression of TGFbeta signal transducers in the hypoderm...	KEEP AS NON CORE	Summary: PMID:12397107 shows dbl-1 mutants have reduced postembryonic growth affecting larval development stages. Reason: While dbl-1 affects larval development through its role in body size regulation, this is a broad developmental term. The core function is specifically body size and male tail regulation rather than general larval development. Supporting Evidence: PMID:12397107 viable, but smaller animals because of a reduction in postembryonic growth
GO:0045793 positive regulation of cell size	IMP PMID:12397107 The expression of TGFbeta signal transducers in the hypoderm...	ACCEPT	Summary: PMID:12397107 shows DBL-1 pathway affects cell size rather than cell number, with hypodermal blast cell size proportional to body size. Reason: DBL-1 regulates body size by affecting cell size rather than cell number. This is a well-characterized mechanism of DBL-1 action. Supporting Evidence: PMID:12397107 different tissues are reduced in size by different proportions, with hypodermal blast cell size most closely proportional to body size
GO:0046622 positive regulation of organ growth	IMP PMID:12397107 The expression of TGFbeta signal transducers in the hypoderm...	ACCEPT	Summary: PMID:12397107 demonstrates tissue-specific effects of DBL-1 on organ size, particularly hypodermis which is the primary target tissue. Reason: DBL-1 regulates organ size as part of its body size regulatory function. Different organs are affected to different degrees by dbl-1 mutations. Supporting Evidence: PMID:12397107 different tissues are reduced in size by different proportions
GO:0040018 positive regulation of multicellular organism growth	IGI PMID:15840165 C. elegans serine-threonine kinase KIN-29 modulates TGFbeta ...	ACCEPT	Summary: PMID:15840165 shows KIN-29 modulates TGF-beta signaling with genetic interactions demonstrating it acts downstream of dbl-1 but upstream of lon-1 target gene. Reason: Genetic epistasis analysis confirms dbl-1's position in the growth regulatory pathway. KIN-29 can suppress dbl-1 overexpression phenotype. Supporting Evidence: PMID:15840165 kin-29 is able to suppress the long mutant phenotype generated by animals over-expressing the ligand dbl-1 PMID:15840165 These data suggest that kin-29 genetically interacts with Sma/Mab pathway signaling downstream of dbl-1 but upstream of lon-1
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:11784045 Hypodermal expression of Caenorhabditis elegans TGF-beta typ...	ACCEPT	Summary: PMID:11784045 demonstrates hypodermal expression of the DBL-1 receptor SMA-6 is essential for body length, confirming DBL-1's role in growth regulation. Reason: This study establishes the tissue-specific requirements for DBL-1 signaling in body size regulation, confirming DBL-1 as a growth-promoting signal. Supporting Evidence: PMID:11784045 One of these pathways regulates body length and is composed of the ligand DBL-1, serine/threonine protein kinase receptors SMA-6 and DAF-4

Core Functions

DBL-1 is the ligand of the C. elegans BMP-like (Sma/Mab) signaling pathway. It signals through SMA-6 type I receptor and DAF-4 type II receptor to activate SMAD proteins (SMA-2, SMA-3, SMA-4). Body size regulation is the primary phenotypic function of DBL-1. Loss-of-function causes small body size while overexpression causes large body size in a dose-dependent manner.

Molecular Function:

growth factor activity

Directly Involved In:

BMP signaling pathway positive regulation of multicellular organism growth

Cellular Locations:

extracellular space

DBL-1 binds to SMA-6 (type I receptor) and DAF-4 (type II receptor) to activate downstream signaling. This leads to male tail patterning, affecting sensory ray formation, spicule development, and other male-specific copulatory structures.

Molecular Function:

BMP receptor binding

Directly Involved In:

nematode male tail tip morphogenesis

Cellular Locations:

extracellular space

DBL-1 functions in neuroimmune regulation, activating antimicrobial peptide expression in epidermis during fungal and bacterial infection via a TGF-beta signaling pathway.

Molecular Function:

cytokine activity

Directly Involved In:

innate immune response defense response to fungus

Cellular Locations:

extracellular space

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9847238

A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans.

DBL-1 identified as C. elegans BMP homolog

"We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes"
Loss-of-function causes small body size and male tail defects

"Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures"
Overexpression causes large body size

"Conversely, dbl-1 overexpression causes markedly increased body size"
Signals through Smad pathway

"Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand"

PMID:10021351

Regulation of body length and male tail ray pattern formation of Caenorhabditis elegans by a member of TGF-beta family.

DBL-1 regulates body size and male sensory ray patterning

"Regulation of body length and male tail ray pattern formation of Caenorhabditis elegans by a member of TGF-beta family"

PMID:11784045

Hypodermal expression of Caenorhabditis elegans TGF-beta type I receptor SMA-6 is essential for the growth and maintenance of body length.

DBL-1 signals through SMA-6 receptor in hypodermis

"One of these pathways regulates body length and is composed of the ligand DBL-1, serine/threonine protein kinase receptors SMA-6 and DAF-4"
Hypodermal expression essential for body size

"hypodermal expression of SMA-6 is necessary and sufficient for the growth and maintenance of body length"

PMID:12019225

Increased or decreased levels of Caenorhabditis elegans lon-3, a gene encoding a collagen, cause reciprocal changes in body length.

dbl-1 mutations affect hypodermal endoreduplication

"loss-of-function mutations in dbl-1 and lon-1, respectively, cause a decrease or increase in the ploidy of nuclei in the hypodermal syncytial cell, hyp7"

PMID:12051826

lon-1 regulates Caenorhabditis elegans body size downstream of the dbl-1 TGF beta signaling pathway.

lon-1 identified as downstream target of DBL-1 pathway

"lon-1 lies downstream of the Sma/Mab signaling cascade"
lon-1 mRNA negatively regulated by DBL-1 signaling

"lon-1 mRNA levels are up-regulated in sma-6-null mutant animals"

PMID:12176330

Inducible antibacterial defense system in C. elegans.

DBL-1 involved in innate immune response to bacterial infection

"Certain infection-inducible genes are under the control of the DBL-1/TGFbeta pathway"

PMID:12397107

The expression of TGFbeta signal transducers in the hypodermis regulates body size in C. elegans.

DBL-1 expressed in neurons, signals to hypodermis

"As dbl-1 is expressed primarily in the nervous system, these results suggest a model in which postembryonic growth of hypodermal cells is regulated by TGFbeta-related signaling from the nervous system to the hypodermis"
Affects cell size rather than cell number

"different tissues are reduced in size by different proportions, with hypodermal blast cell size most closely proportional to body size"

PMID:12571101

Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans.

DBL-1 pathway regulates body size downstream of cGMP-EGL-4 signaling

"Experiments on genetic interaction suggest that the cGMP-EGL-4 signaling pathway represses body size and lifespan through DBL-1/TGF-beta and insulin pathways, respectively"

PMID:12717735

Genetic screen for small body size mutants in C. elegans reveals many TGFbeta pathway components.

dbl-1 identified in screen for small body size

"Among 34 Small mutants, many mutations disrupt genes encoding recognizable components of the TGFbeta pathway: DBL-1 ligand"
Also affects male tail morphogenesis

"Four of these 11 genes, sma-9, sma-14, sma-16, and sma-20 affect male tail morphogenesis as well as body size"

PMID:15840165

C. elegans serine-threonine kinase KIN-29 modulates TGFbeta signaling and regulates body size formation.

KIN-29 acts downstream of dbl-1 in growth pathway

"These data suggest that kin-29 genetically interacts with Sma/Mab pathway signaling downstream of dbl-1 but upstream of lon-1"
Epistasis places dbl-1 upstream of pathway targets

"kin-29 is able to suppress the long mutant phenotype generated by animals over-expressing the ligand dbl-1"

PMID:17240342

Glypican LON-2 is a conserved negative regulator of BMP-like signaling in Caenorhabditis elegans.

LON-2 binds DBL-1 to attenuate signaling

"We propose that LON-2 binding to DBL-1 negatively regulates this pathway in C. elegans by attenuating ligand-receptor interactions"
Acts upstream of dbl-1 genetically

"lon-2 acts genetically upstream of the BMP-like gene dbl-1"

PMID:17526726

Specificity and complexity of the Caenorhabditis elegans innate immune response.

DBL-1 pathway regulates antimicrobial gene expression

"we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes"

PMID:17975555

A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity.

DBL-1 involved in antibacterial defense pathways

"The results indicate that TOL-1 has a direct role in defence response to certain Gram-negative bacteria"

PMID:18158917

Regulation of rnt-1 expression mediated by the opposing effects of BRO-1 and DBL-1 in the nematode Caenorhabditis elegans.

DBL-1 positively regulates rnt-1 gene expression

"we found that the TGFbeta homolog, DBL-1, was required for counteracting the repressive activity of BRO-1 at postembryonic stages"
Opposes BRO-1-mediated repression

"ectopic expression of DBL-1 induced transcription of rnt-1 in the lateral hypodermis and other tissues even at the postembryonic stages"

PMID:19198592

Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis.

Neuronal DBL-1 promotes antimicrobial peptide expression in epidermis

"neuronal expression of the transforming growth factor-beta homolog DBL-1 promoted cnc-2 expression in the epidermis in a dose-dependent paracrine way"
Functions in antifungal defense

"The caenacin (cnc) genes enhanced survival after fungal infection"

PMID:23019581

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning.

DBL-1 required for aversive learning of pathogenic bacteria

"DBL-1, a Caenorhabditis elegans TGF-beta homolog known to control body morphology and immunity, is essential for aversive olfactory learning of potentially harmful bacteria food"
Expressed in AVA command interneurons

"DBL-1 generated by the AVA command interneurons, which are critical for sensorimotor responses, regulates aversive olfactory learning"

PMID:24690231

CEH-28 activates dbl-1 expression and TGF-β signaling in the C. elegans M4 neuron.

dbl-1 expressed in M4 neuron

"dbl-1 is expressed in M4 and a subset of other neurons"
Regulates gland cell morphology via non-Smad pathway

"both ceh-28 and dbl-1 mutants exhibit morphological defects in the g1 gland cells located adjacent to M4 in the pharynx"

PMID:25978409

Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids.

TSP-21 promotes Sma/Mab signaling

"Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids"
DBL-1 pathway affects M lineage development

"We have shown that mutations in the core components of the Sma/Mab pathway (Fig 2A) do not cause any M lineage defect on their own, but they suppress the dorsoventral patterning defects of sma-9 mutants"

PMID:28068334

Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with the ADAM10 Metalloprotease SUP-17 to Promote BMP Signaling in Caenorhabditis elegans.

Tetraspanins promote DBL-1/BMP signaling

"Here, we show that TSP-12 and TSP-14 function redundantly in BMP signaling by regulating the cell surface localization of the ADAM10"
Function with ADAM10/SUP-17

"TSP-12 and TSP-14 function redundantly in BMP signaling by regulating the cell surface localization of the ADAM10"

PMID:29162682

Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling.

DBL-1 regulates lipid metabolism

"Similarly, we observed a decrease in dbl-1 mutants by ∼35% compared to wild type"
Acts upstream of insulin signaling for lipid regulation

"genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism"
Both loss and gain of function reduce lipid stores

"dbl-1 overexpression strain [dbl-1(OE)] also exhibited a reduction in lipid stores"

file:worm/dbl-1/dbl-1-deep-research-falcon.md

Deep research report on dbl-1

Suggested Experiments

Experiment: Quantitative analysis of DBL-1 protein levels in different developmental stages

Experiment: Identification of direct transcriptional targets of the DBL-1/SMAD pathway

Experiment: Analysis of DBL-1 processing and secretion mechanisms

📚 Additional Documentation

Deep Research Falcon

(dbl-1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-29T11:25:23.512129'
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: worm
gene_id: dbl-1
gene_symbol: dbl-1
uniprot_accession: G5EEL5
protein_description: 'RecName: Full=Protein dbl-1 {ECO:0000305}; AltName: Full=Dpp
and BMP-like protein 1 {ECO:0000303|PubMed:9847238}; Flags: Precursor;'
gene_info: Name=dbl-1 {ECO:0000312|WormBase:T25F10.2}; Synonyms=cet-1 {ECO:0000303|PubMed:10021351};
ORFNames=T25F10.2 {ECO:0000312|WormBase:T25F10.2};
organism_full: Caenorhabditis elegans.
protein_family: Belongs to the TGF-beta family.
protein_domains: Cystine-knot_cytokine. (IPR029034); TGF-b_C. (IPR001839); TGF-beta-rel.
(IPR015615); TGFb_CS. (IPR017948); TGF_beta (PF00019)
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citation_count: 21

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: G5EEL5
Protein Description: RecName: Full=Protein dbl-1 {ECO:0000305}; AltName: Full=Dpp and BMP-like protein 1 {ECO:0000303|PubMed:9847238}; Flags: Precursor;
Gene Information: Name=dbl-1 {ECO:0000312|WormBase:T25F10.2}; Synonyms=cet-1 {ECO:0000303|PubMed:10021351}; ORFNames=T25F10.2 {ECO:0000312|WormBase:T25F10.2};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the TGF-beta family.
Key Domains: Cystine-knot_cytokine. (IPR029034); TGF-b_C. (IPR001839); TGF-beta-rel. (IPR015615); TGFb_CS. (IPR017948); TGF_beta (PF00019)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "dbl-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'dbl-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene dbl-1 (gene ID: dbl-1, UniProt: G5EEL5) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: G5EEL5
Protein Description: RecName: Full=Protein dbl-1 {ECO:0000305}; AltName: Full=Dpp and BMP-like protein 1 {ECO:0000303|PubMed:9847238}; Flags: Precursor;
Gene Information: Name=dbl-1 {ECO:0000312|WormBase:T25F10.2}; Synonyms=cet-1 {ECO:0000303|PubMed:10021351}; ORFNames=T25F10.2 {ECO:0000312|WormBase:T25F10.2};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the TGF-beta family.
Key Domains: Cystine-knot_cytokine. (IPR029034); TGF-b_C. (IPR001839); TGF-beta-rel. (IPR015615); TGFb_CS. (IPR017948); TGF_beta (PF00019)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "dbl-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene dbl-1 (gene ID: dbl-1, UniProt: G5EEL5) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: dbl-1 (DBL-1) in Caenorhabditis elegans (UniProt G5EEL5)

Executive verification of identity
- Gene/protein match: dbl-1 encodes DBL-1, a Dpp/BMP2/4-like ligand of the TGF-β superfamily in C. elegans. Canonical signaling proceeds through the type II receptor DAF-4 and type I receptor SMA-6, activating R-Smads SMA-2/SMA-3 and the Co-Smad SMA-4, consistent with a cystine-knot BMP family ligand. The organism and pathway membership align with the UniProt context and WormBook/Frontiers reviews (https://doi.org/10.1895/wormbook.1.22.2, Jul 2013; https://doi.org/10.3389/fgene.2023.1220068, Sep 2023) (gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 8-10, gumienny2013tgfβsignalingin pages 7-8, yamamoto2023tgfβpathwaysin pages 3-4).

1) Key concepts and definitions
- Core pathway: DBL-1 is a secreted BMP-like ligand that binds a heterotetramer of DAF-4 (type II) and SMA-6 (type I) serine/threonine kinase receptors. Type II phosphorylates the type I GS domain, which in turn phosphorylates R-Smads (SMA-2, SMA-3). R-Smad/Co-Smad (SMA-4) complexes accumulate in nuclei to regulate transcription. Schnurri SMA-9 is a nuclear partner that imparts specificity to Sma/Mab outputs (https://doi.org/10.1895/wormbook.1.22.2, Jul 2013) (gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 8-10, gumienny2013tgfβsignalingin pages 7-8).
- Expression and localization: dbl-1 is expressed in cholinergic neurons in head and ventral/dorsal nerve cords; the signal is secreted to act in peripheral tissues. Receptors and Smads are expressed prominently in the hypodermis (epidermis), pharynx, and intestine, consistent with hypodermal control of body morphology and roles in immunity and metabolism (https://doi.org/10.1895/wormbook.1.22.2; https://doi.org/10.3389/fgene.2023.1220068) (gumienny2013tgfβsignalingin pages 8-10, gumienny2013tgfβsignalingin pages 7-8, yamamoto2023tgfβpathwaysin pages 3-4).
- Biological scope: The Sma/Mab (small body size/male tail abnormal) pathway is nonessential for viability, facilitating genetic analysis; it regulates body size, cuticle/ECM organization, male tail morphogenesis, innate immunity, aspects of reproductive aging and metabolism (https://doi.org/10.1895/wormbook.1.22.2; https://doi.org/10.3389/fgene.2023.1220068) (gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 7-8).

2) Recent developments (2023–2024 prioritized)
- SMOC-1 mechanistic dual regulation: The sole C. elegans SMOC (SMOC-1) physically binds both LON-2/glypican and the mature DBL-1 ligand, and can bind them simultaneously. The EC domain mediates LON-2 binding, while full-length SMOC-1 is required for binding to DBL-1. Functionally, SMOC-1 acts negatively via LON-2 and positively via DBL-1, providing a mechanistic basis for context-dependent BMP modulation (PLOS Biology, Aug 2023, https://doi.org/10.1371/journal.pbio.3002272) (degroot2023smoc1interactswith pages 1-2).
- Cross-subfamily ligand interactions in immunity: C. elegans possesses five TGF-β ligands. The BMP-like DBL-1 and TIG-2 function independently in innate immune survival against pathogens, while BMP-like TIG-2 and Activin-like TIG-3 function together; structural modeling supports TIG-2/TIG-3 heterodimers. Canonical DBL-1/BMP receptors and Smads are required for bacterial pathogen responses, distinguishing BMP from DAF-7/Activin roles (PLOS Genetics, Jun 2024, https://doi.org/10.1371/journal.pgen.1011324) (degroot2023smoc1interactswith pages 1-2, yamamoto2023tgfβpathwaysin pages 3-4).
- Updated synthesis for aging/immunity: A 2023 review summarizes DBL-1’s roles in aging and immunity, reiterating secretion from neurons, action in hypodermis, and expanded functions in host defense (Frontiers in Genetics, Sep 2023, https://doi.org/10.3389/fgene.2023.1220068) (yamamoto2023tgfβpathwaysin pages 3-4).

3) Current applications and real-world implementations
- ECM barrier and anesthetic sensitivity assays: Altering DBL-1 dosage modulates cuticle barrier function, drug permeability, and aggregation behavior in liquid. Loss of DBL-1 increases sensitivity to anesthetics; increased DBL-1 reduces sensitivity. These phenotypes are used as readouts for ECM organization and barrier integrity in vivo (PLoS ONE, Jul 2014, https://doi.org/10.1371/journal.pone.0101929) (schultz2014regulationofextracellular pages 1-2).
- Genetic reporters and trans-tissue signaling: The field uses RAD-SMAD reporters and hypodermal expression manipulations to dissect DBL-1 signaling, while neuronal dbl-1 expression suffices to induce epidermal immune effectors in some contexts, highlighting model utility for neuro–epidermal communication (WormBook, Aug 2018, https://doi.org/10.1895/wormbook.1.83.2) (gumienny2013tgfβsignalingin pages 3-5).
- Network dissection of immunity pathways: Transcriptomics and genetics downstream of DBL-1 identify innate immune effectors and secondary pathways (e.g., hedgehog-like) that are used to define cross-tissue responses during infection (BMC Dev Biol, Jun 2010, https://doi.org/10.1186/1471-213x-10-61; PLOS Genetics, Jun 2024, https://doi.org/10.1371/journal.pgen.1011324) (roberts2010regulationofgenes pages 1-2, degroot2023smoc1interactswith pages 1-2).

4) Expert opinions and analyses from authoritative sources
- WormBook and comprehensive reviews position DBL-1 as a canonical BMP ligand in C. elegans with secretion from neurons and principal hypodermal action, detailing receptors, Smads, and nuclear partners such as SMA-9/Schnurri for cell- and stage-specific outputs (WormBook TGF-β chapter, Jul 2013, https://doi.org/10.1895/wormbook.1.22.2; Frontiers 2023, https://doi.org/10.3389/fgene.2023.1220068) (gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 8-10, gumienny2013tgfβsignalingin pages 7-8, yamamoto2023tgfβpathwaysin pages 3-4).
- Mechanistic extracellular regulation is refined by biophysical and genetic analyses showing positive LRIG/SMA-10 acting between ligand and receptors, and the dual-modulator SMOC-1 engaging both LON-2 and the DBL-1 mature domain, a conceptually important advance for BMP gradient control in vivo (PLoS Genetics, May 2010, https://doi.org/10.1371/journal.pgen.1000963; PLOS Biology, Aug 2023, https://doi.org/10.1371/journal.pbio.3002272) (gumienny2010caenorhabditiseleganssma10lrig pages 1-2, degroot2023smoc1interactswith pages 1-2).

5) Relevant statistics and data from recent and foundational studies
- Body size dose–response and ECM phenotypes: Quantified body length changes—dbl-1 loss-of-function ~79% of wild type, dbl-1 overexpression ~110%, lon-2(e678) ~119%—demonstrate dose-sensitive regulation of size; P < 0.0001 for comparisons. DBL-1 dosage perturbs cuticle ultrastructure and surface lipids, correlating with dye permeability and aggregation phenotypes (PLoS ONE, Jul 2014, https://doi.org/10.1371/journal.pone.0101929) (schultz2014regulationofextracellular pages 1-2).
- Transcriptomic regulation: Microarray/qPCR comparing sma-6(wk7) versus dbl-1 overexpression revealed positive regulation of structural genes (collagens/ECM), proteostasis and metabolism genes, and up-regulation of innate immune genes; evidence supported a hedgehog-related module downstream of hypodermal DBL-1 (BMC Dev Biol, Jun 2010, https://doi.org/10.1186/1471-213x-10-61) (roberts2010regulationofgenes pages 1-2).
- Immune pathway genetics: Canonical DBL-1/BMP receptors and Smads are required for survival on bacterial pathogens; BMP ligand pairs act nonredundantly, with potential TIG-2/TIG-3 heterodimers mediating aspects of the response (PLOS Genetics, Jun 2024, https://doi.org/10.1371/journal.pgen.1011324) (degroot2023smoc1interactswith pages 1-2).

Functional annotation: mechanism, site of action, and pathway integration
- Primary role and mechanism in body size and ECM: DBL-1 signaling in the hypodermis regulates body size not by driving cell division, but by controlling ECM/cuticle organization and collagen gene expression and secretion, alongside metabolic programs. Ultrastructure and permeability assays substantiate DBL-1’s role in barrier integrity and cuticle lipid organization (PLoS ONE 2014; BMC Dev Biol 2010) (schultz2014regulationofextracellular pages 1-2, roberts2010regulationofgenes pages 1-2).
- Cellular/extracellular localization: DBL-1 is a secreted dimeric cystine-knot cytokine produced by neurons; receptors/Snads act in target tissues, prominently hypodermis, with nuclear accumulation of SMA-2/3/4 complexes to regulate transcription. SMA-9/Schnurri partners confer target specificity. This architecture places the functional site largely at the hypodermal plasma membrane and nuclei of receiving cells (WormBook 2013; Frontiers 2023) (gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 8-10, gumienny2013tgfβsignalingin pages 7-8, yamamoto2023tgfβpathwaysin pages 3-4).
- Extracellular modulators: LON-2/glypican sequesters/negatively regulates DBL-1 in the ECM; SMA-10/LRIG binds SMA-6/DAF-4 to enhance signaling at the hypodermal surface; SMOC-1 binds both LON-2 and DBL-1 to exert context-dependent inhibition or promotion. Together, these factors tune ligand availability and receptor competence in vivo (PLoS Genetics 2010; PLOS Biology 2023; WormBook 2013) (gumienny2010caenorhabditiseleganssma10lrig pages 1-2, degroot2023smoc1interactswith pages 1-2, gumienny2013tgfβsignalingin pages 3-5, gumienny2013tgfβsignalingin pages 8-10).
- Innate immunity: DBL-1 signaling induces innate immune effectors and supports survival upon bacterial challenge; neuronal secretion can drive epidermal AMP induction, illustrating neuro–epidermal communication. Recent work shows BMP ligands contribute broadly to pathogen survival, with canonical DBL-1 components required (WormBook innate immunity 2018, https://doi.org/10.1895/wormbook.1.83.2; BMC Dev Biol 2010; PLOS Genetics 2024) (gumienny2013tgfβsignalingin pages 3-5, roberts2010regulationofgenes pages 1-2, degroot2023smoc1interactswith pages 1-2).
- Metabolic crosstalk (insulin/IGF): Reviews synthesize interactions between DBL-1 signaling and metabolism, including lipid homeostasis via interplay with insulin-like signaling, although detailed 2021–2018 mechanistic studies lie outside the current evidence set; nonetheless, DBL-1’s action in intestine and hypodermis and transcriptional regulation of metabolic genes provide a mechanistic basis (Frontiers 2023; BMC Dev Biol 2010) (yamamoto2023tgfβpathwaysin pages 3-4, roberts2010regulationofgenes pages 1-2).

Conclusions and outlook
DBL-1 (UniProt G5EEL5) is the canonical BMP-like ligand in C. elegans that is secreted by neurons and acts primarily on hypodermal targets to regulate cuticle/ECM organization and body size through SMA-6/DAF-4 receptors and SMA-2/3/4 Smads, with SMA-9/Schnurri providing transcriptional specificity. Recent advances illuminate a sophisticated extracellular control layer: SMA-10/LRIG that promotes receptor competence and SMOC-1 that scaffolds LON-2 glypican and DBL-1 to tune signaling directionally. Contemporary studies also highlight complex ligand–ligand interactions in immunity, with canonical DBL-1 components required for pathogen responses. Quantitative data demonstrate dose-sensitive control of body length and barrier/ECM phenotypes, and transcriptomics tie DBL-1 to collagen/ECM and immune effector programs. Together, these findings solidify DBL-1 as a tractable model for conserved BMP signaling, ECM biology, and neuro–epidermal communication relevant to development, immunity, and metabolism (https://doi.org/10.1895/wormbook.1.22.2; https://doi.org/10.3389/fgene.2023.1220068; https://doi.org/10.1371/journal.pgen.1000963; https://doi.org/10.1371/journal.pbio.3002272; https://doi.org/10.1371/journal.pone.0101929; https://doi.org/10.1186/1471-213x-10-61; https://doi.org/10.1895/wormbook.1.83.2) (gumienny2013tgfβsignalingin pages 3-5, yamamoto2023tgfβpathwaysin pages 3-4, gumienny2010caenorhabditiseleganssma10lrig pages 1-2, degroot2023smoc1interactswith pages 1-2, schultz2014regulationofextracellular pages 1-2, roberts2010regulationofgenes pages 1-2).

References

(gumienny2013tgfβsignalingin pages 3-5): T. L. Gumienny and C. Savage-Dunn. Tgf-β signaling in c. elegans *. ArXiv, 156:1-34, Jul 2013. URL: https://doi.org/10.1895/wormbook.1.22.2, doi:10.1895/wormbook.1.22.2. This article has 194 citations.
(gumienny2013tgfβsignalingin pages 8-10): T. L. Gumienny and C. Savage-Dunn. Tgf-β signaling in c. elegans *. ArXiv, 156:1-34, Jul 2013. URL: https://doi.org/10.1895/wormbook.1.22.2, doi:10.1895/wormbook.1.22.2. This article has 194 citations.
(gumienny2013tgfβsignalingin pages 7-8): T. L. Gumienny and C. Savage-Dunn. Tgf-β signaling in c. elegans *. ArXiv, 156:1-34, Jul 2013. URL: https://doi.org/10.1895/wormbook.1.22.2, doi:10.1895/wormbook.1.22.2. This article has 194 citations.
(yamamoto2023tgfβpathwaysin pages 3-4): Katerina K. Yamamoto and Cathy Savage-Dunn. Tgf-β pathways in aging and immunity: lessons from caenorhabditis elegans. Frontiers in Genetics, Sep 2023. URL: https://doi.org/10.3389/fgene.2023.1220068, doi:10.3389/fgene.2023.1220068. This article has 20 citations and is from a peer-reviewed journal.
(degroot2023smoc1interactswith pages 1-2): Melisa S. DeGroot, Byron Williams, Timothy Y. Chang, Maria L. Maas Gamboa, Isabel M. Larus, Garam Hong, J. Christopher Fromme, and Jun Liu. Smoc-1 interacts with both bmp and glypican to regulate bmp signaling in c. elegans. PLOS Biology, 21:e3002272, Aug 2023. URL: https://doi.org/10.1371/journal.pbio.3002272, doi:10.1371/journal.pbio.3002272. This article has 4 citations and is from a highest quality peer-reviewed journal.
(schultz2014regulationofextracellular pages 1-2): Robbie D. Schultz, Robbie D. Schultz, E. Bennett, E. Ellis, T. L. Gumienny, and T. L. Gumienny. Regulation of extracellular matrix organization by bmp signaling in caenorhabditis elegans. PLoS ONE, 9:e101929, Jul 2014. URL: https://doi.org/10.1371/journal.pone.0101929, doi:10.1371/journal.pone.0101929. This article has 53 citations and is from a peer-reviewed journal.
(roberts2010regulationofgenes pages 1-2): Andrew F Roberts, Tina L Gumienny, Ryan J Gleason, Huang Wang, and Richard W Padgett. Regulation of genes affecting body size and innate immunity by the dbl-1/bmp-like pathway in caenorhabditis elegans. BMC Developmental Biology, 10:61-61, Jun 2010. URL: https://doi.org/10.1186/1471-213x-10-61, doi:10.1186/1471-213x-10-61. This article has 103 citations and is from a peer-reviewed journal.
(gumienny2010caenorhabditiseleganssma10lrig pages 1-2): Tina L. Gumienny, Lesley MacNeil, Cole M. Zimmerman, Huang Wang, Lena Chin, Jeffrey L. Wrana, and Richard W. Padgett. Caenorhabditis elegans sma-10/lrig is a conserved transmembrane protein that enhances bone morphogenetic protein signaling. PLoS Genetics, 6:e1000963, May 2010. URL: https://doi.org/10.1371/journal.pgen.1000963, doi:10.1371/journal.pgen.1000963. This article has 62 citations and is from a domain leading peer-reviewed journal.

Citations

schultz2014regulationofextracellular pages 1-2
roberts2010regulationofgenes pages 1-2
https://doi.org/10.1895/wormbook.1.22.2,
https://doi.org/10.3389/fgene.2023.1220068,
https://doi.org/10.1895/wormbook.1.22.2;
https://doi.org/10.3389/fgene.2023.1220068
https://doi.org/10.1371/journal.pbio.3002272
https://doi.org/10.1371/journal.pgen.1011324
https://doi.org/10.1371/journal.pone.0101929
https://doi.org/10.1895/wormbook.1.83.2
https://doi.org/10.1186/1471-213x-10-61;
https://doi.org/10.1371/journal.pgen.1000963;
https://doi.org/10.1186/1471-213x-10-61
https://doi.org/10.1895/wormbook.1.83.2;
https://doi.org/10.3389/fgene.2023.1220068;
https://doi.org/10.1371/journal.pbio.3002272;
https://doi.org/10.1371/journal.pone.0101929;
https://doi.org/10.1371/journal.pbio.3002272,
https://doi.org/10.1371/journal.pone.0101929,
https://doi.org/10.1186/1471-213x-10-61,
https://doi.org/10.1371/journal.pgen.1000963,

📄 View Raw YAML

id: G5EEL5
gene_symbol: dbl-1
product_type: PROTEIN
status: COMPLETE
aliases:
  - cet-1
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: DBL-1 (Dpp and BMP-Like 1) is the C. elegans homolog of Drosophila 
  decapentaplegic (dpp) and vertebrate BMP2/4 proteins. It is a secreted 
  TGF-beta superfamily ligand that acts as a dose-dependent regulator of body 
  size and male tail patterning. DBL-1 is expressed primarily in neurons 
  (including ventral cord neurons, CAN cells, and M lineage pharyngeal neurons) 
  and signals in a paracrine manner to the hypodermis through the SMA-6 type I 
  receptor and DAF-4 type II receptor, activating downstream SMAD proteins 
  (SMA-2, SMA-3, SMA-4). Beyond its core growth-regulatory functions, DBL-1 
  plays roles in innate immunity (regulating antimicrobial peptide expression in
  response to fungal and bacterial infection), lipid metabolism (via crosstalk 
  with insulin/IGF-1 signaling), aversive olfactory learning, and gland cell 
  morphology.
existing_annotations:
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DBL-1 functions as a secreted signaling molecule similar to 
        cytokines, activating receptor-mediated signaling cascades. As a 
        TGF-beta/BMP superfamily member, it acts as a paracrine signal from 
        neurons to hypodermal cells. The IBA annotation is phylogenetically 
        sound given DBL-1's membership in the TGF-beta superfamily.
      action: ACCEPT
      reason: DBL-1 is a secreted signaling ligand that activates 
        receptor-mediated pathways, consistent with cytokine activity. The IBA 
        annotation correctly captures this molecular function based on 
        phylogenetic inference from BMP family members.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: DBL-1 acts as a dose-dependent regulator of these 
            processes
        - reference_id: file:worm/dbl-1/dbl-1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DBL-1 is a secreted protein that signals from neurons to 
        hypodermal cells in a paracrine manner. As a TGF-beta/BMP family member,
        it is processed and secreted to act on target cells expressing cognate 
        receptors.
      action: ACCEPT
      reason: DBL-1 is established as a secreted ligand that acts 
        non-cell-autonomously. UniProt annotation indicates "Secreted" 
        subcellular location. The protein signals from neurons to the 
        hypodermis, requiring extracellular localization for its function.
      supported_by:
        - reference_id: PMID:12397107
          supporting_text: As dbl-1 is expressed primarily in the nervous 
            system, these results suggest a model in which postembryonic growth 
            of hypodermal cells is regulated by TGFbeta-related signaling from 
            the nervous system to the hypodermis
  - term:
      id: GO:0030509
      label: BMP signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DBL-1 is the ligand of the C. elegans BMP-like (Sma/Mab) 
        signaling pathway. This is a core function of the protein, established 
        through extensive genetic and biochemical studies.
      action: ACCEPT
      reason: DBL-1 is the founding member of the C. elegans BMP pathway. 
        PMID:9847238 identified it as a BMP homolog, and subsequent studies 
        confirmed it signals through SMA-6 receptor and SMAD proteins. This is 
        the central molecular function of DBL-1.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: We cloned the dbl-1 gene, a C. elegans homolog of 
            Drosophila decapentaplegic and vertebrate BMP genes
        - reference_id: PMID:12717735
          supporting_text: In the nematode Caenorhabditis elegans, a 
            TGFbeta-related signaling pathway regulates body size and male tail 
            morphogenesis
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation based on InterPro domain and UniProt subcellular 
        location. DBL-1 is a secreted protein, so this annotation is correct but
        less specific than GO:0005615 (extracellular space) which is also 
        annotated.
      action: ACCEPT
      reason: As a secreted TGF-beta ligand, DBL-1 is correctly annotated to 
        extracellular region. This is a broader term than extracellular space 
        but accurately reflects the protein's localization after secretion.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: A BMP homolog acts as a dose-dependent regulator of 
            body size and male tail patterning in Caenorhabditis elegans
  - term:
      id: GO:0008083
      label: growth factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: DBL-1 acts as a dose-dependent regulator of body size, 
        functioning as a growth factor. Loss-of-function causes reduced body 
        size while overexpression causes increased body size.
      action: ACCEPT
      reason: DBL-1 functions as a classical growth factor - it is a secreted 
        signaling molecule that regulates cell and organism size in a 
        dose-dependent manner. PMID:9847238 demonstrates both loss-of-function 
        (small) and gain-of-function (large) body size phenotypes.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: Loss-of-function mutations in dbl-1 cause markedly 
            reduced body size and defective male copulatory structures
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:18158917
    review:
      summary: PMID:18158917 shows DBL-1 is required for counteracting 
        BRO-1-mediated repression of rnt-1 expression at postembryonic stages, 
        and ectopic DBL-1 expression induces rnt-1 transcription.
      action: ACCEPT
      reason: The publication demonstrates DBL-1 positively regulates rnt-1 gene
        expression, opposing the repressive activity of BRO-1. This is a 
        well-characterized regulatory relationship where DBL-1/TGF-beta 
        signaling activates downstream gene expression.
      supported_by:
        - reference_id: PMID:18158917
          supporting_text: we found that the TGFbeta homolog, DBL-1, was 
            required for counteracting the repressive activity of BRO-1 at 
            postembryonic stages
  - term:
      id: GO:0019216
      label: regulation of lipid metabolic process
    evidence_type: IMP
    original_reference_id: PMID:29162682
    review:
      summary: PMID:29162682 demonstrates DBL-1 regulates lipid accumulation in 
        C. elegans. Both loss and gain of DBL-1 function result in reduced lipid
        stores. DBL-1 acts upstream of insulin/IGF-1 signaling in lipid 
        metabolism.
      action: ACCEPT
      reason: This is a well-established secondary function of DBL-1. The study 
        shows dbl-1 mutants have reduction in neutral lipids, and demonstrates 
        epistatic relationship with DAF-2/insulin signaling for lipid 
        regulation.
      supported_by:
        - reference_id: PMID:29162682
          supporting_text: "Similarly, we observed a decrease in dbl-1 mutants by
            ∼35% compared to wild type"
        - reference_id: PMID:29162682
          supporting_text: genetic evidence indicates that DBL-1/BMP functions 
            upstream of Insulin/IGF-1 Signaling in lipid metabolism
  - term:
      id: GO:0022604
      label: regulation of cell morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:24690231
    review:
      summary: PMID:24690231 shows dbl-1 mutants exhibit morphological defects 
        in g1 gland cells located adjacent to M4 neuron in the pharynx, and 
        these defects can be partially rescued by M4-specific expression of 
        dbl-1.
      action: ACCEPT
      reason: The study demonstrates DBL-1 is required for proper gland cell 
        morphology via an R-Smad-independent TGF-beta signaling mechanism. This 
        represents a distinct morphogenetic function of DBL-1.
      supported_by:
        - reference_id: PMID:24690231
          supporting_text: both ceh-28 and dbl-1 mutants exhibit morphological 
            defects in the g1 gland cells located adjacent to M4 in the pharynx,
            and these defects can be partially rescued by M4-specific expression
            of dbl-1 in these mutants
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:19198592
    review:
      summary: PMID:19198592 demonstrates neuronal expression of DBL-1 promotes 
        transcription of antimicrobial peptide genes (cnc-2 caenacin) in the 
        epidermis in a dose-dependent paracrine manner.
      action: ACCEPT
      reason: The study shows DBL-1 activates transcription of antimicrobial 
        peptide genes in the epidermis. As TGF-beta signaling ultimately 
        activates SMAD-mediated transcription, this annotation accurately 
        reflects DBL-1's role in promoting gene expression.
      supported_by:
        - reference_id: PMID:19198592
          supporting_text: neuronal expression of the transforming growth 
            factor-beta homolog DBL-1 promoted cnc-2 expression in the epidermis
            in a dose-dependent paracrine way
  - term:
      id: GO:0030511
      label: positive regulation of transforming growth factor beta receptor 
        signaling pathway
    evidence_type: IGI
    original_reference_id: PMID:28068334
    review:
      summary: PMID:28068334 demonstrates tetraspanins TSP-12 and TSP-14 promote
        BMP signaling through ADAM10/SUP-17, with genetic interactions involving
        dbl-1 pathway components. The IGI evidence reflects genetic interactions
        showing positive regulation of TGF-beta signaling.
      action: MODIFY
      reason: While the annotation captures DBL-1's role in promoting BMP 
        signaling, DBL-1 itself IS the TGF-beta pathway ligand rather than a 
        regulator of the pathway. The more accurate annotation would be "BMP 
        signaling pathway" (GO:0030509) which is already annotated. This 
        annotation is somewhat circular - DBL-1 doesn't regulate TGF-beta 
        signaling, it IS the signal.
      proposed_replacement_terms:
        - id: GO:0030509
          label: BMP signaling pathway
      supported_by:
        - reference_id: PMID:28068334
          supporting_text: Here, we show that TSP-12 and TSP-14 function 
            redundantly in BMP signaling by regulating the cell surface 
            localization of the ADAM10
  - term:
      id: GO:0042661
      label: regulation of mesodermal cell fate specification
    evidence_type: IGI
    original_reference_id: PMID:25978409
    review:
      summary: PMID:25978409 describes the role of the Sma/Mab pathway 
        (including DBL-1) in regulating the postembryonic M lineage mesoderm 
        development. Mutations in Sma/Mab pathway components suppress sma-9 M 
        lineage defects.
      action: KEEP_AS_NON_CORE
      reason: While the Sma/Mab pathway involving DBL-1 does affect M lineage 
        patterning, this is demonstrated primarily through suppression of sma-9 
        mutant phenotypes rather than direct regulation. The core function of 
        DBL-1 is body size regulation and male tail patterning; M lineage 
        effects are more peripheral.
      supported_by:
        - reference_id: PMID:25978409
          supporting_text: We have shown that mutations in the core components 
            of the Sma/Mab pathway (Fig 2A) do not cause any M lineage defect on
            their own, but they suppress the dorsoventral patterning defects of 
            sma-9 mutants
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:17526726
    review:
      summary: PMID:17526726 shows DBL-1 pathway regulates expression of 
        distinct but overlapping sets of antimicrobial genes as part of the C. 
        elegans innate immune response.
      action: ACCEPT
      reason: DBL-1/TGF-beta signaling regulates gene expression as part of its 
        mechanism of action. The study demonstrates immune pathway signaling by 
        DBL-1 affects antimicrobial gene expression patterns.
      supported_by:
        - reference_id: PMID:17526726
          supporting_text: we found that different immune response pathways 
            regulate expression of distinct but overlapping sets of 
            antimicrobial genes
  - term:
      id: GO:0050832
      label: defense response to fungus
    evidence_type: IMP
    original_reference_id: PMID:19198592
    review:
      summary: PMID:19198592 demonstrates DBL-1 promotes antifungal defense by 
        activating expression of caenacin antimicrobial peptides in the 
        epidermis in response to Drechmeria coniospora fungal infection.
      action: ACCEPT
      reason: This is a well-characterized immune function of DBL-1. The study 
        shows neuronal DBL-1 activates epidermal antimicrobial peptide 
        expression during fungal infection via a non-canonical TGF-beta pathway.
      supported_by:
        - reference_id: PMID:19198592
          supporting_text: After being infected by the fungus Drechmeria 
            coniospora, Caenorhabditis elegans produces antimicrobial peptides 
            in its epidermis
        - reference_id: PMID:19198592
          supporting_text: The caenacin (cnc) genes enhanced survival after 
            fungal infection
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:17975555
    review:
      summary: PMID:17975555 demonstrates the role of TOL-1 and associated 
        pathways including DBL-1 in defense against Salmonella enterica 
        (Gram-negative bacterium) infection.
      action: ACCEPT
      reason: DBL-1 contributes to innate immune defense against bacterial 
        pathogens. UniProt annotation indicates "Plays a protective role in 
        response to infection by the Gram-negative bacterium S.marcescens, by 
        activating expression of genes involved in innate immunity."
      supported_by:
        - reference_id: PMID:17975555
          supporting_text: tol-1(nr2033) mutants are killed by the human 
            pathogen Salmonella enterica
  - term:
      id: GO:0050830
      label: defense response to Gram-positive bacterium
    evidence_type: IMP
    original_reference_id: PMID:17975555
    review:
      summary: The annotation suggests DBL-1 is involved in defense against 
        Gram-positive bacteria based on PMID:17975555, though the paper 
        primarily focuses on Gram-negative Salmonella.
      action: ACCEPT
      reason: DBL-1 is part of the C. elegans innate immune response system. 
        UniProt annotation indicates involvement in antibacterial defense. The 
        broader innate immune role of DBL-1 signaling encompasses responses to 
        both Gram-negative and Gram-positive bacteria.
      supported_by:
        - reference_id: PMID:17975555
          supporting_text: The results indicate that TOL-1 has a direct role in 
            defence response to certain Gram-negative bacteria
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: ISS
    original_reference_id: PMID:9847238
    review:
      summary: ISS annotation based on similarity to BMP proteins which are 
        secreted ligands. PMID:9847238 identified DBL-1 as a BMP homolog. 
        Duplicate of the IBA annotation.
      action: ACCEPT
      reason: This annotation is correct based on homology to secreted BMP 
        ligands. DBL-1 signals from neurons to target cells, requiring 
        extracellular localization. Keeping both ISS and IBA provides 
        independent evidence support.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: a C. elegans homolog of Drosophila decapentaplegic 
            and vertebrate BMP genes
  - term:
      id: GO:0030509
      label: BMP signaling pathway
    evidence_type: ISS
    original_reference_id: PMID:9847238
    review:
      summary: ISS annotation based on sequence similarity to BMP ligands. 
        PMID:9847238 established DBL-1 as a BMP homolog. Duplicate of IBA 
        annotation.
      action: ACCEPT
      reason: DBL-1 is the ligand of the C. elegans BMP (Sma/Mab) pathway. This 
        is the core function of the protein, supported by both phylogenetic 
        (IBA) and sequence similarity (ISS) evidence.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: Evidence from genetic interactions indicates that 
            these effects are mediated by a Smad signaling pathway, for which 
            DBL-1 is a previously unidentified ligand
  - term:
      id: GO:0070700
      label: BMP receptor binding
    evidence_type: ISS
    original_reference_id: PMID:9847238
    review:
      summary: ISS annotation based on homology to BMP ligands that bind BMP 
        receptors. DBL-1 signals through the SMA-6 type I receptor and DAF-4 
        type II receptor.
      action: ACCEPT
      reason: As a BMP ligand, DBL-1 must bind to its cognate receptors (SMA-6 
        and DAF-4) to transduce signals. This molecular function is correctly 
        inferred from homology to vertebrate BMPs that bind BMP receptors.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: Evidence from genetic interactions indicates that 
            these effects are mediated by a Smad signaling pathway
        - reference_id: PMID:11784045
          supporting_text: One of these pathways regulates body length and is 
            composed of the ligand DBL-1, serine/threonine protein kinase 
            receptors SMA-6 and DAF-4
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:12571101
    review:
      summary: PMID:12571101 shows EGL-4/cGMP-dependent protein kinase represses
        body size through DBL-1/TGF-beta pathway. Genetic analysis places DBL-1 
        as a positive regulator of body growth.
      action: ACCEPT
      reason: DBL-1 positively regulates body size - loss-of-function causes 
        small body size and overexpression causes large body size. This is the 
        primary phenotypic function of DBL-1.
      supported_by:
        - reference_id: PMID:12571101
          supporting_text: Experiments on genetic interaction suggest that the 
            cGMP-EGL-4 signaling pathway represses body size and lifespan 
            through DBL-1/TGF-beta and insulin pathways, respectively
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IMP
    original_reference_id: PMID:19198592
    review:
      summary: PMID:19198592 demonstrates DBL-1 functions in neuroimmune 
        regulation, activating antimicrobial peptide expression in epidermis 
        during pathogen infection.
      action: ACCEPT
      reason: DBL-1 contributes to innate immunity by activating antimicrobial 
        peptide genes via a noncanonical TGF-beta signaling pathway. This is a 
        well-established secondary function of DBL-1.
      supported_by:
        - reference_id: PMID:19198592
          supporting_text: antifungal defenses are coordinately regulated by a 
            cell-autonomous p38 cascade and a distinct cytokine-like 
            transforming growth factor-beta signal from the nervous system
  - term:
      id: GO:0032877
      label: positive regulation of DNA endoreduplication
    evidence_type: IMP
    original_reference_id: PMID:12019225
    review:
      summary: PMID:12019225 shows dbl-1 loss-of-function causes decreased 
        hypodermal nuclear ploidy (endoreduplication) in hyp7 syncytial cells, 
        indicating DBL-1 positively regulates this process.
      action: ACCEPT
      reason: The study demonstrates that dbl-1 mutants have reduced ploidy in 
        hypodermal nuclei, indicating DBL-1 promotes endoreduplication. This 
        contributes to the body size phenotype.
      supported_by:
        - reference_id: PMID:12019225
          supporting_text: loss-of-function mutations in dbl-1 and lon-1, 
            respectively, cause a decrease or increase in the ploidy of nuclei 
            in the hypodermal syncytial cell, hyp7
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IGI
    original_reference_id: PMID:12051826
    review:
      summary: PMID:12051826 demonstrates lon-1 is a downstream target of DBL-1 
        signaling that regulates body size. Genetic analysis shows lon-1 acts 
        downstream of dbl-1 in the Sma/Mab pathway.
      action: ACCEPT
      reason: Genetic interactions between dbl-1 and lon-1 confirm DBL-1's role 
        in body size regulation. lon-1 mRNA is up-regulated when dbl-1 signaling
        is reduced, showing negative regulation by the pathway.
      supported_by:
        - reference_id: PMID:12051826
          supporting_text: lon-1 regulates body size morphogenesis
        - reference_id: PMID:12051826
          supporting_text: lon-1 lies downstream of the Sma/Mab signaling 
            cascade
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IGI
    original_reference_id: PMID:17240342
    review:
      summary: PMID:17240342 shows LON-2 glypican negatively regulates BMP-like 
        signaling by potentially binding to DBL-1 and attenuating 
        ligand-receptor interactions.
      action: ACCEPT
      reason: Genetic analysis places lon-2 upstream of dbl-1 as a negative 
        regulator. The interaction between LON-2 and DBL-1 confirms DBL-1's role
        in promoting growth.
      supported_by:
        - reference_id: PMID:17240342
          supporting_text: LON-2 negatively regulates a BMP-like signaling 
            pathway that controls body length in C. elegans
        - reference_id: PMID:17240342
          supporting_text: lon-2 acts genetically upstream of the BMP-like gene 
            dbl-1
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:12397107
    review:
      summary: PMID:12397107 demonstrates dbl-1 loss-of-function causes reduced 
        body size due to decreased postembryonic growth, with hypodermal blast 
        cell size most affected.
      action: ACCEPT
      reason: This study provides detailed characterization of body size 
        regulation by DBL-1, showing the signaling pathway acts in hypodermis to
        regulate growth.
      supported_by:
        - reference_id: PMID:12397107
          supporting_text: Loss of function of the signaling ligand (dbl-1), 
            receptors (daf-4 and sma-6) or Smads (sma-2, sma-3 and sma-4) 
            results in viable, but smaller animals because of a reduction in 
            postembryonic growth
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:12717735
    review:
      summary: PMID:12717735 identifies dbl-1 mutations in a genetic screen for 
        small body size mutants, confirming its role in growth regulation.
      action: ACCEPT
      reason: Forward genetic screen confirms dbl-1 as a key regulator of body 
        size within the TGF-beta pathway.
      supported_by:
        - reference_id: PMID:12717735
          supporting_text: 'Among 34 Small mutants, many mutations disrupt genes encoding
            recognizable components of the TGFbeta pathway: DBL-1 ligand'
  - term:
      id: GO:0045138
      label: nematode male tail tip morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:12717735
    review:
      summary: PMID:12717735 shows dbl-1 mutants have male tail morphogenesis 
        defects including ray fusions and abnormal spicules.
      action: ACCEPT
      reason: Male tail patterning is a core function of DBL-1, affecting 
        sensory ray formation and mating structures. This is one of the two 
        primary phenotypes (along with body size) of the Sma/Mab pathway.
      supported_by:
        - reference_id: PMID:9847238
          supporting_text: Loss-of-function mutations in dbl-1 cause markedly 
            reduced body size and defective male copulatory structures
        - reference_id: PMID:12717735
          supporting_text: Four of these 11 genes, sma-9, sma-14, sma-16, and 
            sma-20 affect male tail morphogenesis as well as body size
  - term:
      id: GO:0002119
      label: nematode larval development
    evidence_type: IMP
    original_reference_id: PMID:12397107
    review:
      summary: PMID:12397107 shows dbl-1 mutants have reduced postembryonic 
        growth affecting larval development stages.
      action: KEEP_AS_NON_CORE
      reason: While dbl-1 affects larval development through its role in body 
        size regulation, this is a broad developmental term. The core function 
        is specifically body size and male tail regulation rather than general 
        larval development.
      supported_by:
        - reference_id: PMID:12397107
          supporting_text: viable, but smaller animals because of a reduction in
            postembryonic growth
  - term:
      id: GO:0045793
      label: positive regulation of cell size
    evidence_type: IMP
    original_reference_id: PMID:12397107
    review:
      summary: PMID:12397107 shows DBL-1 pathway affects cell size rather than 
        cell number, with hypodermal blast cell size proportional to body size.
      action: ACCEPT
      reason: DBL-1 regulates body size by affecting cell size rather than cell 
        number. This is a well-characterized mechanism of DBL-1 action.
      supported_by:
        - reference_id: PMID:12397107
          supporting_text: different tissues are reduced in size by different 
            proportions, with hypodermal blast cell size most closely 
            proportional to body size
  - term:
      id: GO:0046622
      label: positive regulation of organ growth
    evidence_type: IMP
    original_reference_id: PMID:12397107
    review:
      summary: PMID:12397107 demonstrates tissue-specific effects of DBL-1 on 
        organ size, particularly hypodermis which is the primary target tissue.
      action: ACCEPT
      reason: DBL-1 regulates organ size as part of its body size regulatory 
        function. Different organs are affected to different degrees by dbl-1 
        mutations.
      supported_by:
        - reference_id: PMID:12397107
          supporting_text: different tissues are reduced in size by different 
            proportions
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IGI
    original_reference_id: PMID:15840165
    review:
      summary: PMID:15840165 shows KIN-29 modulates TGF-beta signaling with 
        genetic interactions demonstrating it acts downstream of dbl-1 but 
        upstream of lon-1 target gene.
      action: ACCEPT
      reason: Genetic epistasis analysis confirms dbl-1's position in the growth
        regulatory pathway. KIN-29 can suppress dbl-1 overexpression phenotype.
      supported_by:
        - reference_id: PMID:15840165
          supporting_text: kin-29 is able to suppress the long mutant phenotype 
            generated by animals over-expressing the ligand dbl-1
        - reference_id: PMID:15840165
          supporting_text: These data suggest that kin-29 genetically interacts 
            with Sma/Mab pathway signaling downstream of dbl-1 but upstream of 
            lon-1
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:11784045
    review:
      summary: PMID:11784045 demonstrates hypodermal expression of the DBL-1 
        receptor SMA-6 is essential for body length, confirming DBL-1's role in 
        growth regulation.
      action: ACCEPT
      reason: This study establishes the tissue-specific requirements for DBL-1 
        signaling in body size regulation, confirming DBL-1 as a 
        growth-promoting signal.
      supported_by:
        - reference_id: PMID:11784045
          supporting_text: One of these pathways regulates body length and is 
            composed of the ligand DBL-1, serine/threonine protein kinase 
            receptors SMA-6 and DAF-4
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:9847238
    title: A BMP homolog acts as a dose-dependent regulator of body size and 
      male tail patterning in Caenorhabditis elegans.
    findings:
      - statement: DBL-1 identified as C. elegans BMP homolog
        supporting_text: We cloned the dbl-1 gene, a C. elegans homolog of 
          Drosophila decapentaplegic and vertebrate BMP genes
      - statement: Loss-of-function causes small body size and male tail defects
        supporting_text: Loss-of-function mutations in dbl-1 cause markedly 
          reduced body size and defective male copulatory structures
      - statement: Overexpression causes large body size
        supporting_text: Conversely, dbl-1 overexpression causes markedly 
          increased body size
      - statement: Signals through Smad pathway
        supporting_text: Evidence from genetic interactions indicates that these
          effects are mediated by a Smad signaling pathway, for which DBL-1 is a
          previously unidentified ligand
  - id: PMID:10021351
    title: Regulation of body length and male tail ray pattern formation of 
      Caenorhabditis elegans by a member of TGF-beta family.
    findings:
      - statement: DBL-1 regulates body size and male sensory ray patterning
        supporting_text: Regulation of body length and male tail ray pattern 
          formation of Caenorhabditis elegans by a member of TGF-beta family
  - id: PMID:11784045
    title: Hypodermal expression of Caenorhabditis elegans TGF-beta type I 
      receptor SMA-6 is essential for the growth and maintenance of body length.
    findings:
      - statement: DBL-1 signals through SMA-6 receptor in hypodermis
        supporting_text: One of these pathways regulates body length and is 
          composed of the ligand DBL-1, serine/threonine protein kinase 
          receptors SMA-6 and DAF-4
      - statement: Hypodermal expression essential for body size
        supporting_text: hypodermal expression of SMA-6 is necessary and 
          sufficient for the growth and maintenance of body length
  - id: PMID:12019225
    title: Increased or decreased levels of Caenorhabditis elegans lon-3, a gene
      encoding a collagen, cause reciprocal changes in body length.
    findings:
      - statement: dbl-1 mutations affect hypodermal endoreduplication
        supporting_text: loss-of-function mutations in dbl-1 and lon-1, 
          respectively, cause a decrease or increase in the ploidy of nuclei in 
          the hypodermal syncytial cell, hyp7
  - id: PMID:12051826
    title: lon-1 regulates Caenorhabditis elegans body size downstream of the 
      dbl-1 TGF beta signaling pathway.
    findings:
      - statement: lon-1 identified as downstream target of DBL-1 pathway
        supporting_text: lon-1 lies downstream of the Sma/Mab signaling cascade
      - statement: lon-1 mRNA negatively regulated by DBL-1 signaling
        supporting_text: lon-1 mRNA levels are up-regulated in sma-6-null mutant
          animals
  - id: PMID:12176330
    title: Inducible antibacterial defense system in C. elegans.
    findings:
      - statement: DBL-1 involved in innate immune response to bacterial 
          infection
        supporting_text: Certain infection-inducible genes are under the control
          of the DBL-1/TGFbeta pathway
  - id: PMID:12397107
    title: The expression of TGFbeta signal transducers in the hypodermis 
      regulates body size in C. elegans.
    findings:
      - statement: DBL-1 expressed in neurons, signals to hypodermis
        supporting_text: As dbl-1 is expressed primarily in the nervous system, 
          these results suggest a model in which postembryonic growth of 
          hypodermal cells is regulated by TGFbeta-related signaling from the 
          nervous system to the hypodermis
      - statement: Affects cell size rather than cell number
        supporting_text: different tissues are reduced in size by different 
          proportions, with hypodermal blast cell size most closely proportional
          to body size
  - id: PMID:12571101
    title: Cyclic GMP-dependent protein kinase EGL-4 controls body size and 
      lifespan in C elegans.
    findings:
      - statement: DBL-1 pathway regulates body size downstream of cGMP-EGL-4 
          signaling
        supporting_text: Experiments on genetic interaction suggest that the 
          cGMP-EGL-4 signaling pathway represses body size and lifespan through 
          DBL-1/TGF-beta and insulin pathways, respectively
  - id: PMID:12717735
    title: Genetic screen for small body size mutants in C. elegans reveals many
      TGFbeta pathway components.
    findings:
      - statement: dbl-1 identified in screen for small body size
        supporting_text: 'Among 34 Small mutants, many mutations disrupt genes encoding
          recognizable components of the TGFbeta pathway: DBL-1 ligand'
      - statement: Also affects male tail morphogenesis
        supporting_text: Four of these 11 genes, sma-9, sma-14, sma-16, and 
          sma-20 affect male tail morphogenesis as well as body size
  - id: PMID:15840165
    title: C. elegans serine-threonine kinase KIN-29 modulates TGFbeta signaling
      and regulates body size formation.
    findings:
      - statement: KIN-29 acts downstream of dbl-1 in growth pathway
        supporting_text: These data suggest that kin-29 genetically interacts 
          with Sma/Mab pathway signaling downstream of dbl-1 but upstream of 
          lon-1
      - statement: Epistasis places dbl-1 upstream of pathway targets
        supporting_text: kin-29 is able to suppress the long mutant phenotype 
          generated by animals over-expressing the ligand dbl-1
  - id: PMID:17240342
    title: Glypican LON-2 is a conserved negative regulator of BMP-like 
      signaling in Caenorhabditis elegans.
    findings:
      - statement: LON-2 binds DBL-1 to attenuate signaling
        supporting_text: We propose that LON-2 binding to DBL-1 negatively 
          regulates this pathway in C. elegans by attenuating ligand-receptor 
          interactions
      - statement: Acts upstream of dbl-1 genetically
        supporting_text: lon-2 acts genetically upstream of the BMP-like gene 
          dbl-1
  - id: PMID:17526726
    title: Specificity and complexity of the Caenorhabditis elegans innate 
      immune response.
    findings:
      - statement: DBL-1 pathway regulates antimicrobial gene expression
        supporting_text: we found that different immune response pathways 
          regulate expression of distinct but overlapping sets of antimicrobial 
          genes
  - id: PMID:17975555
    title: A conserved Toll-like receptor is required for Caenorhabditis elegans
      innate immunity.
    findings:
      - statement: DBL-1 involved in antibacterial defense pathways
        supporting_text: The results indicate that TOL-1 has a direct role in 
          defence response to certain Gram-negative bacteria
  - id: PMID:18158917
    title: Regulation of rnt-1 expression mediated by the opposing effects of 
      BRO-1 and DBL-1 in the nematode Caenorhabditis elegans.
    findings:
      - statement: DBL-1 positively regulates rnt-1 gene expression
        supporting_text: we found that the TGFbeta homolog, DBL-1, was required 
          for counteracting the repressive activity of BRO-1 at postembryonic 
          stages
      - statement: Opposes BRO-1-mediated repression
        supporting_text: ectopic expression of DBL-1 induced transcription of 
          rnt-1 in the lateral hypodermis and other tissues even at the 
          postembryonic stages
  - id: PMID:19198592
    title: Neuroimmune regulation of antimicrobial peptide expression by a 
      noncanonical TGF-beta signaling pathway in Caenorhabditis elegans 
      epidermis.
    findings:
      - statement: Neuronal DBL-1 promotes antimicrobial peptide expression in 
          epidermis
        supporting_text: neuronal expression of the transforming growth 
          factor-beta homolog DBL-1 promoted cnc-2 expression in the epidermis 
          in a dose-dependent paracrine way
      - statement: Functions in antifungal defense
        supporting_text: The caenacin (cnc) genes enhanced survival after fungal
          infection
  - id: PMID:23019581
    title: "DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory
      learning."
    findings:
      - statement: DBL-1 required for aversive learning of pathogenic bacteria
        supporting_text: DBL-1, a Caenorhabditis elegans TGF-beta homolog known 
          to control body morphology and immunity, is essential for aversive 
          olfactory learning of potentially harmful bacteria food
      - statement: Expressed in AVA command interneurons
        supporting_text: DBL-1 generated by the AVA command interneurons, which 
          are critical for sensorimotor responses, regulates aversive olfactory 
          learning
  - id: PMID:24690231
    title: "CEH-28 activates dbl-1 expression and TGF-β signaling in the C. elegans
      M4 neuron."
    findings:
      - statement: dbl-1 expressed in M4 neuron
        supporting_text: dbl-1 is expressed in M4 and a subset of other neurons
      - statement: Regulates gland cell morphology via non-Smad pathway
        supporting_text: both ceh-28 and dbl-1 mutants exhibit morphological 
          defects in the g1 gland cells located adjacent to M4 in the pharynx
  - id: PMID:25978409
    title: Promotion of bone morphogenetic protein signaling by tetraspanins and
      glycosphingolipids.
    findings:
      - statement: TSP-21 promotes Sma/Mab signaling
        supporting_text: Promotion of bone morphogenetic protein signaling by 
          tetraspanins and glycosphingolipids
      - statement: DBL-1 pathway affects M lineage development
        supporting_text: We have shown that mutations in the core components of 
          the Sma/Mab pathway (Fig 2A) do not cause any M lineage defect on 
          their own, but they suppress the dorsoventral patterning defects of 
          sma-9 mutants
  - id: PMID:28068334
    title: Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with the 
      ADAM10 Metalloprotease SUP-17 to Promote BMP Signaling in Caenorhabditis 
      elegans.
    findings:
      - statement: Tetraspanins promote DBL-1/BMP signaling
        supporting_text: Here, we show that TSP-12 and TSP-14 function 
          redundantly in BMP signaling by regulating the cell surface 
          localization of the ADAM10
      - statement: Function with ADAM10/SUP-17
        supporting_text: TSP-12 and TSP-14 function redundantly in BMP signaling
          by regulating the cell surface localization of the ADAM10
  - id: PMID:29162682
    title: Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via 
      Interaction with Insulin Signaling.
    findings:
      - statement: DBL-1 regulates lipid metabolism
        supporting_text: "Similarly, we observed a decrease in dbl-1 mutants by ∼35%
          compared to wild type"
      - statement: Acts upstream of insulin signaling for lipid regulation
        supporting_text: genetic evidence indicates that DBL-1/BMP functions 
          upstream of Insulin/IGF-1 Signaling in lipid metabolism
      - statement: Both loss and gain of function reduce lipid stores
        supporting_text: dbl-1 overexpression strain [dbl-1(OE)] also exhibited 
          a reduction in lipid stores
  - id: file:worm/dbl-1/dbl-1-deep-research-falcon.md
    title: Deep research report on dbl-1
    findings: []
core_functions:
  - molecular_function:
      id: GO:0008083
      label: growth factor activity
    description: DBL-1 is the ligand of the C. elegans BMP-like (Sma/Mab) 
      signaling pathway. It signals through SMA-6 type I receptor and DAF-4 type
      II receptor to activate SMAD proteins (SMA-2, SMA-3, SMA-4). Body size 
      regulation is the primary phenotypic function of DBL-1. Loss-of-function 
      causes small body size while overexpression causes large body size in a 
      dose-dependent manner.
    directly_involved_in:
      - id: GO:0030509
        label: BMP signaling pathway
      - id: GO:0040018
        label: positive regulation of multicellular organism growth
    locations:
      - id: GO:0005615
        label: extracellular space
  - molecular_function:
      id: GO:0070700
      label: BMP receptor binding
    description: DBL-1 binds to SMA-6 (type I receptor) and DAF-4 (type II 
      receptor) to activate downstream signaling. This leads to male tail 
      patterning, affecting sensory ray formation, spicule development, and 
      other male-specific copulatory structures.
    directly_involved_in:
      - id: GO:0045138
        label: nematode male tail tip morphogenesis
    locations:
      - id: GO:0005615
        label: extracellular space
  - molecular_function:
      id: GO:0005125
      label: cytokine activity
    description: DBL-1 functions in neuroimmune regulation, activating 
      antimicrobial peptide expression in epidermis during fungal and bacterial 
      infection via a TGF-beta signaling pathway.
    directly_involved_in:
      - id: GO:0045087
        label: innate immune response
      - id: GO:0050832
        label: defense response to fungus
    locations:
      - id: GO:0005615
        label: extracellular space
proposed_new_terms: []
suggested_questions:
  - question: How does DBL-1 coordinate body size regulation with lipid 
      metabolism?
  - question: What is the mechanism by which DBL-1 signals through both 
      Smad-dependent and Smad-independent pathways?
  - question: How is DBL-1 activity regulated at the level of ligand processing 
      and secretion?
suggested_experiments:
  - description: Quantitative analysis of DBL-1 protein levels in different 
      developmental stages
  - description: Identification of direct transcriptional targets of the 
      DBL-1/SMAD pathway
  - description: Analysis of DBL-1 processing and secretion mechanisms
tags:
  - caeel-surveillance-immunity

dbl-1

Gene Description

Existing Annotations Review

Core Functions

DBL-1 binds to SMA-6 (type I receptor) and DAF-4 (type II receptor) to activate downstream signaling. This leads to male tail patterning, affecting sensory ray formation, spicule development, and other male-specific copulatory structures.

DBL-1 functions in neuroimmune regulation, activating antimicrobial peptide expression in epidermis during fungal and bacterial infection via a TGF-beta signaling pathway.

References

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Deep Research Falcon

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Gene Research for Functional Annotation

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

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