LAG-2 is a transmembrane Delta/Serrate/LAG-2 (DSL) family ligand for the Caenorhabditis elegans Notch receptors LIN-12 and GLP-1. It is a single-pass type I membrane protein with an N-terminal region and DSL domain that engage the receptor EGF repeats; its own EGF-like repeats are dispensable for activity. LAG-2 lacks the DOS motif, which can be supplied in trans by secreted DOS-motif co-ligands such as OSM-11. LAG-2 is expressed by the distal tip cell and its processes. There it forms the germline stem-cell niche signal that activates GLP-1 to maintain germline proliferation. It is also the lateral signal in LIN-12-mediated decisions, including the anchor cell/ventral uterine decision, vulval precursor cell patterning, and ventral M-lineage fates. It acts partly redundantly with APX-1 and DSL-1, which can substitute for it. Secreted, truncated extracellular forms of LAG-2 retain signaling activity. During vulval development lag-2 is transcribed specifically in P6.p in response to the inductive EGFR/Ras/MAPK (LET-23) signal, which relieves LIN-1-mediated repression of the lag-2 promoter; its transcription also requires UNC-62 and the Mediator subunit SUR-2. This couples inductive and lateral signalling in vulval precursor cell patterning.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | ACCEPT | Summary: Cell fate specification IBA (PTN000505678); lag-2 itself is a donor. Reason: LAG-2 is the signal-sending ligand in many LIN-12/GLP-1 cell-fate decisions. lag-2's own experimental annotation grounds this IBA. Supporting Evidence: PMID:14701877 Two initially equivalent cells interact via the receptor LIN-12 and its ligand LAG-2, so that one becomes the AC and the other a VU. |
| GO:0001708 cell fate specification | IEA GO_REF:0000002 | ACCEPT | Summary: Cell fate specification (InterPro IEA). Reason: Correct. Supporting Evidence: PMID:1769331 we have identified two genes, lag-1 and lag-2, that appear to be required for both lin-12 and glp-1-mediated cell interactions |
| GO:0001708 cell fate specification | IMP PMID:14701877 Post-transcriptional regulation of the E/Daughterless orthol... | ACCEPT | Summary: LAG-2 is the signal in the AC/VU decision. Reason: Direct genetic evidence; LAG-2 is the ligand that mediates lateral specification. Supporting Evidence: PMID:14701877 Two initially equivalent cells interact via the receptor LIN-12 and its ligand LAG-2, so that one becomes the AC and the other a VU. |
| GO:0001708 cell fate specification | IMP PMID:15282161 Multiple roles for the E/Daughterless ortholog HLH-2 during ... | ACCEPT | Summary: lag-2 RNAi disrupts somatic gonad cell fate decisions. Reason: Consistent with the LAG-2 ligand role in the AC/VU decision. Supporting Evidence: PMID:15282161 HLH-2 has been implicated in cell fate specification in different neural lineages and in the LIN-12/Notch-mediated anchor cell (AC)/ventral uterine precursor cell (VU) decision in the somatic gonad. |
| GO:0001708 cell fate specification | IMP PMID:1769331 Two homologous regulatory genes, lin-12 and glp-1, have over... | ACCEPT | Summary: Strong lag-2 mutants phenocopy lin-12 glp-1 double mutants. Reason: LAG-2 is required for both LIN-12- and GLP-1-mediated cell-fate decisions. Supporting Evidence: PMID:1769331 we have identified two genes, lag-1 and lag-2, that appear to be required for both lin-12 and glp-1-mediated cell interactions PMID:1769331 Strong loss-of-function lag mutants are phenotypically indistinguishable from the lin-12 glp-1 double |
| GO:0002119 nematode larval development | IMP PMID:1769331 Two homologous regulatory genes, lin-12 and glp-1, have over... | KEEP AS NON CORE | Summary: Strong lag-2 mutants arrest as L1 larvae. Reason: Pleiotropic consequence of failed embryonic cell-fate decisions. Supporting Evidence: PMID:1769331 Strong loss-of-function lag mutants are phenotypically indistinguishable from the lin-12 glp-1 double |
| GO:0005112 Notch binding | IBA GO_REF:0000033 | ACCEPT | Summary: Notch binding IBA from PTN000505678, grounded in C. elegans DSL ligand donors including lag-2 itself. Reason: LAG-2 is a canonical DSL ligand for LIN-12 and GLP-1. Core molecular function. Supporting Evidence: PMID:18700817 we first confirmed that the extracellular domain of LAG-2 PMID:18700817 interact with LIN-12 extracellular EGF repeats 1 through 6 in the two-hybrid assay |
| GO:0005112 Notch binding | IEA GO_REF:0000002 | ACCEPT | Summary: Notch binding (InterPro DSL-domain IEA). Reason: Correct. Supporting Evidence: PMID:7607081 lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor |
| GO:0005112 Notch binding | IPI PMID:18700817 OSM-11 facilitates LIN-12 Notch signaling during Caenorhabdi... | ACCEPT | Summary: The LAG-2 extracellular domain binds LIN-12 EGF repeats 1-6 in yeast two-hybrid. Reason: Direct interaction evidence for Notch binding. Supporting Evidence: PMID:18700817 we first confirmed that the extracellular domain of LAG-2 PMID:18700817 interact with LIN-12 extracellular EGF repeats 1 through 6 in the two-hybrid assay |
| GO:0005886 plasma membrane | IDA PMID:7607081 lag-2 may encode a signaling ligand for the GLP-1 and LIN-12... | ACCEPT | Summary: LAG-2 membrane protein expressed in the DTC. Reason: Consistent with a transmembrane DSL ligand. Supporting Evidence: PMID:7607081 lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (UniProt subcellular location IEA). Reason: Correct. Supporting Evidence: PMID:7607081 lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor |
| GO:0007154 cell communication | IEA GO_REF:0000002 | ACCEPT | Summary: Cell communication (IEA from DSL domain). Reason: Correct but general; Notch signaling is more specific. Supporting Evidence: PMID:7607081 we propose that lag-2 may encode a signaling ligand for GLP-1/LIN-12 |
| GO:0007219 Notch signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Notch signaling pathway (IEA). Reason: LAG-2 initiates signaling as the ligand. Supporting Evidence: PMID:7607081 we propose that lag-2 may encode a signaling ligand for GLP-1/LIN-12 |
| GO:0008406 gonad development | IMP PMID:15282161 Multiple roles for the E/Daughterless ortholog HLH-2 during ... | KEEP AS NON CORE | Summary: lag-2 RNAi affects somatic gonad development. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:15282161 hlh-2 also acts at an independent point in the gonadal lineage both to specify distal tip cells (DTCs) and in DTC differentiation and function |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane (IEA). Reason: Correct but general. Supporting Evidence: PMID:7607081 lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor |
| GO:0030431 sleep | IMP PMID:29523076 Normal sleep bouts are not essential for C. elegans survival... | KEEP AS NON CORE | Summary: Reduced LAG-2 increases time in developmental sleep bouts. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:29523076 Reduced function of Notch ligand LAG-2 or JNK-1 kinase resulted in increased time in sleep bouts during development. |
| GO:0031253 cell projection membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Cell projection membrane IBA; lag-2 is the donor. Reason: LAG-2 is found on DTC processes that contact germ cells. Supporting Evidence: PMID:16672375 DTC processes were scored in fixed germ lines extruded from worms carrying either qIs56 ( lag-2::GFP) or qEx318 ( lag-2::LAG-2::MYC) and stained with either anti-GFP or anti-MYC. |
| GO:0031253 cell projection membrane | IDA PMID:16672375 Cellular analyses of the mitotic region in the Caenorhabditi... | ACCEPT | Summary: LAG-2::MYC on distal tip cell processes. Reason: Direct observation that the ligand is on the niche processes contacting germline stem cells. Supporting Evidence: PMID:16672375 DTC processes were scored in fixed germ lines extruded from worms carrying either qIs56 ( lag-2::GFP) or qEx318 ( lag-2::LAG-2::MYC) and stained with either anti-GFP or anti-MYC. PMID:16672375 a lag-2::LAG-2::MYC translational reporter reveals functional LAG-2 protein within the DTC (this work) |
| GO:0031253 cell projection membrane | IDA PMID:8575327 Interchangeability of Caenorhabditis elegans DSL proteins an... | ACCEPT | Summary: LAG-2 on cell processes. Reason: Consistent with DTC-process localization; defer to curator. Supporting Evidence: PMID:8575327 Here we show that APX-1 can fully substitute for LAG-2 when expressed under the control of lag-2 regulatory sequences. |
| GO:0032809 neuronal cell body membrane | IDA PMID:16672375 Cellular analyses of the mitotic region in the Caenorhabditi... | MODIFY | Summary: LAG-2 on the membrane of the distal tip cell body. Reason: The DTC is a somatic gonadal (niche) cell, not a neuron, so neuronal cell body membrane is the wrong term. The observation supports plasma membrane of the DTC. Proposed replacements: plasma membrane Supporting Evidence: PMID:16672375 a lag-2::LAG-2::MYC translational reporter reveals functional LAG-2 protein within the DTC (this work) |
| GO:0032809 neuronal cell body membrane | IDA PMID:8575327 Interchangeability of Caenorhabditis elegans DSL proteins an... | MODIFY | Summary: LAG-2 at the cell body membrane. Reason: As for the parallel annotation: the lag-2-expressing cells assayed (DTC and gonadal cells) are not neurons. Plasma membrane is the appropriate location term. Proposed replacements: plasma membrane Supporting Evidence: PMID:8575327 Here we show that APX-1 can fully substitute for LAG-2 when expressed under the control of lag-2 regulatory sequences. |
| GO:0040028 regulation of vulval development | IMP PMID:1769331 Two homologous regulatory genes, lin-12 and glp-1, have over... | KEEP AS NON CORE | Summary: lag-2 alleles affect vulval development. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:1769331 Strong loss-of-function lag mutants are phenotypically indistinguishable from the lin-12 glp-1 double |
| GO:0042661 regulation of mesodermal cell fate specification | IMP PMID:18036582 Dorsoventral patterning of the C. elegans postembryonic meso... | KEEP AS NON CORE | Summary: LAG-2 (with APX-1) promotes ventral M-lineage fates. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:18036582 its ligands LAG-2 and APX-1 are asymmetrically localized in cells adjacent to ventral M-derived cells, and may function redundantly in promoting ventral M lineage fates |
| GO:0043055 maintenance of dauer | IGI PMID:18599512 Notch signalling is required for both dauer maintenance and ... | KEEP AS NON CORE | Summary: LAG-2 with GLP-1 maintains dauer. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:18599512 we demonstrate that glp-1, one of the two C. elegans Notch receptors, and its ligand lag-2 are expressed in neurons during the dauer stage, and both genes are required to maintain this stage in a daf-7/TGFbeta dauer constitutive background |
| GO:0110011 regulation of basement membrane organization | IMP PMID:27661254 Boundary cells restrict dystroglycan trafficking to control ... | KEEP AS NON CORE | Summary: LAG-2 in the AC activates LIN-12 in pi cells to promote BM sliding. Reason: Supported developmental/physiological context of LAG-2 signaling; downstream output rather than a core molecular activity. Supporting Evidence: PMID:27661254 LIN-29 maintains the expression of the transmembrane Notch ligand LAG-2 in the AC, which activates LIN-12 in the neighboring ventral uterine cells and specifies the Ο cell fate |
| GO:1905936 regulation of germ cell proliferation | IMP PMID:19502484 MSP and GLP-1/Notch signaling coordinately regulate actomyos... | ACCEPT | Summary: LAG-2 from the DTC regulates germline proliferation and oocyte growth via GLP-1. Reason: The DTC-derived LAG-2 signal to GLP-1 is the niche signal controlling germ cell proliferation. Supporting Evidence: PMID:19502484 proper oocyte growth depends on distal tip cell signaling involving the redundant function of GLP-1 ligands LAG-2 and APX-1 PMID:7607081 we show that the lag-2 promoter drives expression of a reporter protein in the signaling distal tip cell (DTC) of the DTC/germline interaction |
| GO:2000648 positive regulation of stem cell proliferation | IMP PMID:1769331 Two homologous regulatory genes, lin-12 and glp-1, have over... | ACCEPT | Summary: lag-2 is required for GLP-1-mediated germline proliferation. Reason: LAG-2 is the niche ligand that keeps germline stem cells proliferating. Supporting Evidence: PMID:1769331 we have identified two genes, lag-1 and lag-2, that appear to be required for both lin-12 and glp-1-mediated cell interactions |
| GO:0048018 receptor ligand activity | IMP PMID:8575327 Interchangeability of Caenorhabditis elegans DSL proteins an... | NEW | Summary: LAG-2 extracellular domain activates LIN-12 and GLP-1; secreted truncated forms activate the receptors ectopically in vivo. Reason: NEW, complementing Notch binding (GO:0005112): LAG-2 is the activating DSL ligand of the distal tip cell niche and of LIN-12 lateral signaling, and in vivo its extracellular domain activates LIN-12 and GLP-1. Comparator check: Drosophila Dl and Ser and human DLL1 and JAG1 carry GO:0048018 for the same role. Supporting Evidence: PMID:8575327 Moreover, we provide evidence that these truncated forms are secreted and able to activate LIN-12 and GLP-1 ectopically. |
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Download this section (compressed HTML)Q: Does LAG-2 require an endogenous DOS-motif co-ligand (OSM-11/OSM-7 family) for GLP-1 activation in the germline niche, as proposed for LIN-12 in vulval development?
Q: Is the neuronal cell body membrane annotation for LAG-2 a mapping error for the distal tip cell body?
Experiment: Measure direct LAG-2 DSL-domain binding affinity for LIN-12 versus GLP-1 EGF repeats, with and without OSM-11, using purified proteins.
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