col1a1a (collagen type I alpha 1a; the chihuahua locus) encodes the pro-alpha1(I) chain of zebrafish type I collagen, the main fibrillar collagen of bone, skin, scales, tendons and ligaments. It is one of two zebrafish co-orthologs of human COL1A1 that arose in the teleost-specific genome duplication; its paralog col1a1b encodes the teleost alpha3(I) chain. The 1447-aa secreted procollagen has the fibrillar collagen architecture of a signal peptide, an N-propeptide with a von Willebrand factor type C domain, an uninterrupted Gly-X-Y triple-helical domain and a C-terminal fibrillar collagen NC1 (C-propeptide) domain that drives chain recognition and trimer assembly. Its product associates with alpha2(I) (col1a2) and alpha3(I) (col1a1b) chains into type I collagen trimers that self-assemble into banded fibrils of the extracellular matrix; in adult bone, skin and scales the three chains occur at about equal amounts. col1a1a is co-expressed with col1a1b and col1a2 in osteoblasts, tendon and ligament fibroblasts, myosepta and basal epidermis, but it is the only type I collagen gene expressed in the median fin fold and pectoral fin margin, where alpha1(I) homotrimers contribute to actinotrichia. Loss of col1a1a is lethal in larvae (uninflated swim bladder, absent actinotrichia), and dominant glycine substitutions (chihuahua, dmh13, dmh14) cause osteogenesis imperfecta-like short stature, fractures, vertebral deformities and abnormal mineralization, and disrupt fin development and regeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001501 skeletal system development | IMP PMID:28835471 Genetic Screen for Postembryonic Development in the Zebrafis... | ACCEPT | Summary: Genotype col1a1a^dmh13/+ (ZFIN). dmh13 is a dominant glycine substitution (G1093R) in the col1a1a triple helix, isolated in an adult forward screen for short stature, with vertebral deformation and excessive bone formation. Reason: Type I collagen is the main organic component of bone matrix, and dominant helix glycine substitutions in the col1a1a chain produce skeletal dysplasia, as in human COL1A1-related osteogenesis imperfecta. The col1a1a chain contributes structure to the skeletal matrix, so this is a direct role, and human COL1A1 carries the same term by IMP. Supporting Evidence: PMID:28835471 Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked, while the dmh29 mutants exhibit mutations in a glycine residue of the col1a1b gene (G1123D), leading to a very similar phenotype. |
| GO:0001501 skeletal system development | IMP PMID:28835471 Genetic Screen for Postembryonic Development in the Zebrafis... | ACCEPT | Summary: Genotype col1a1a^dmh14/+ (G1144E), the second dominant col1a1a allele from the same adult screen, with the same short-stature and vertebral phenotype class. Reason: As for dmh13: a dominant helix glycine substitution in the col1a1a chain disrupts skeletal development, consistent with the structural role of type I collagen in bone. Supporting Evidence: PMID:28835471 Interestingly, in this phenotypic class, we were able to identify dominant mutations in all components of Collagen I |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: Genotype col1a1a^dc124/+ (chihuahua). In the micro-CT phenomic survey, chi/+ fish have short stature, kyphoscoliosis, vertebral malformation and fractures, modelling moderate-to-severe dominant osteogenesis imperfecta. Reason: Direct evidence from a col1a1a allele that the alpha1(I) chain is required for normal skeletal development; the chain supplies the collagen framework of bone. Supporting Evidence: PMID:30082390 The col1a1achi/+ mutant, reported earlier (21, 35), carries the same mutation that was identified in a human patient with severe and heavily deforming OI type III (34), and also displays a moderate to severe phenotype with skeletal malformation, including shorter vertebral bodies, kyphoscoliosis, and evidence of fractures |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: Genotype col1a1a^dmh13/+, re-examined by micro-CT phenomics in the type I collagen mutant survey. Reason: A col1a1a allele with a skeletal phenotype; same reasoning as the PMID:28835471 row for this allele. Supporting Evidence: PMID:30082390 The col1a1admh13, col1a1admh14, col1a1bdmh29, and col1a2dmh15 mutant fish were generated in a forward genetics screen (40). |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: The supporting genotype of this row, ZDB-GENO-180503-7, is col1a1b^dmh29/+ (ZFIN genotype page, checked 2026-09-28). It carries a col1a1b allele and no col1a1a lesion; in the paper, dmh29 is listed as an alpha3(I) (col1a1b) glycine substitution. Reason: The claim is true: the rows backed by col1a1a alleles (dc124, dmh13, dmh14, sa1748) are ACCEPTed for this term. This row's evidence is a col1a1b mutant, so it is attached to the wrong gene; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. The same evidence belongs on col1a1b, which already carries skeletal system development IMP for this genotype from PMID:28835471. Supporting Evidence: PMID:28835471 Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked PMID:28835471 Analysis by microcomputed tomography (ΞΌCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: The supporting genotype of this row, ZDB-GENO-180503-8, is col1a2^dmh15/+ (ZFIN genotype page, checked 2026-09-28): an alpha2(I) glycine substitution, with no col1a1a lesion. Reason: The claim is true: the rows backed by col1a1a alleles are ACCEPTed for this term. This row's evidence is a col1a2 mutant, so it is attached to the wrong gene; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. Supporting Evidence: PMID:28835471 Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked PMID:28835471 Analysis by microcomputed tomography (ΞΌCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: Genotype col1a1a^dmh14/+, re-examined by micro-CT phenomics. Reason: A col1a1a allele with a skeletal phenotype; same reasoning as the PMID:28835471 row for this allele. Supporting Evidence: PMID:30082390 The alleles dmh13, dmh14, and dmh29 all cluster in the major ligand binding region 3 of type I collagen |
| GO:0001501 skeletal system development | IMP PMID:30082390 Zebrafish type I collagen mutants faithfully recapitulate hu... | ACCEPT | Summary: Genotype col1a1a^sa1748/+; col1a1b^sa12931/+ (double heterozygous nonsense alleles). Either single heterozygote is normal, but the double heterozygote has a mild osteogenesis imperfecta type I-like phenotype with rib fractures, scoliosis and vertebral compression. Reason: Valid evidence for both paralogs: the phenotype appears only when the combined dose of alpha1(I) and alpha3(I) is reduced. This is the key evidence that the two chains act together, and partly interchangeably, in bone collagen. Supporting Evidence: PMID:30082390 Hence, we generated a double-heterozygous knockout mutant (col1a1a+/β;col1a1b+/β), which displays a mild skeletal phenotype, with a low frequency of spontaneous fractures (calluses in the ribs), scoliosis and localized compression, fusions, and mild malformation of the vertebral bodies in some of the mutant fish |
| GO:0005201 extracellular matrix structural constituent | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro2GO/UniRule mapping from the fibrillar collagen C-terminal domain (IPR000885). Reason: Correct but general. The more specific child GO:0030020 (conferring tensile strength) is present by IBA and is used in core_functions. A broader IEA is acceptable alongside it. Supporting Evidence: PMID:26876635 As collagen type I is the major structural protein in bone and skin |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated location from ARBA/UniRule; the procollagen has a signal peptide and is secreted. Reason: Correct, if general; the specific location is the extracellular matrix (GO:0031012, IBA). Supporting Evidence: PMID:26876635 Following secretion, specific peptidases are responsible for the removal of the N- and C-propeptides, allowing the mature triple helix to self-assemble into fibrils. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | REMOVE | Summary: IBA from PTN002771199, whose only listed experimental source is col1a1a itself (ZFIN:ZDB-GENE-030131-9102), i.e. the IDA cytoplasm row from PMID:19757382 reviewed below. Reason: The node's only grounding is an mRNA in situ hybridization in which col1a1 was used as a keratinocyte marker. mRNA localization does not show where the protein acts. Type I collagen chains act in the extracellular matrix. The procollagen passes through the endoplasmic reticulum lumen during synthesis, but that is not where its structural activity is exerted, so "is active in cytoplasm" misplaces the function. No fibrillar collagen in the family has experimental evidence of cytoplasmic activity to support placing this at an ancestral node. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE EVIDENCE WEAK COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002771199 Β· PTN002771199 SOURCE WEAK OR INFERRED The node's only listed experimental source is zebrafish col1a1a itself, so the IBD rests on a single mRNA-level observation. ZFIN:ZDB-GENE-030131-9102 Β· col1a1a SOURCE BAD Source IDA (PMID:19757382) is a col1a1 mRNA in situ used as a keratinocyte marker, not a protein localization; the protein acts in the extracellular matrix. Supporting Evidence: PMID:19757382 double fluorescent in situ hybridizations for grhl1 and the keratinocyte markers collagen 1a1 PMID:26876635 In the endoplasmic reticulum, type I collagen is synthesized as a pro-collagen molecule |
| GO:0005737 cytoplasm | IDA PMID:19757382 Zebrafish grainyhead-like1 is a common marker of different n... | MARK AS OVER ANNOTATED | Summary: The paper is about grhl1-expressing epidermal cell lineages. The full text was read. col1a1 appears only as an mRNA probe marking basal keratinocytes in double fluorescent in situ hybridization. No col1a1 protein localization is reported. Reason: The staining localizes col1a1 transcripts, not the protein. The claim is not strictly false: nascent procollagen sits in the endoplasmic reticulum, which GO places within the cytoplasm. But it is uninformative about where the protein acts, and it has been propagated by IBA to both paralogs. The informative location is the extracellular matrix. Marked as over-annotated rather than removed, because the figures could not be inspected. Supporting Evidence: PMID:19757382 double fluorescent in situ hybridizations for grhl1 and the keratinocyte markers collagen 1a1 |
| GO:0030020 extracellular matrix structural constituent conferring tensile strength | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of the core molecular function of fibrillar and network collagens. Reason: This is the core molecular function of a type I collagen chain. Loss of alpha1(I) is lethal and removes actinotrichia, and the chain is a major component of bone, skin and scale collagen. Supporting Evidence: PMID:26876635 We demonstrated that, both in zebrafish embryos and adult tissues, three instead of two types of alpha chains contribute to the formation of the collagen type I triple helix PMID:30082390 Eventually, all genotypes containing a homozygous knockout of col1a1a [loss of Ξ±1(I)] were found to be lethal by the age of 3 mo. |
| GO:0030199 collagen fibril organization | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for fibrillar collagen chains. col1a1a is among the sources, via its own IMP from PMID:35282456; this is expected, not circular. Reason: Fibrillar collagen chains are the building blocks of the fibrils. The chain does part of the work of fibril organization (the structure case), and chihuahua shows abnormal fibril packing. Supporting Evidence: PMID:26876635 allowing the mature triple helix to self-assemble into fibrils |
| GO:0030199 collagen fibril organization | IMP PMID:35282456 Compression Fractures and Partial Phenotype Rescue With a Lo... | ACCEPT | Summary: Chihuahua (col1a1a^dc124/+). Transmission electron microscopy shows densely packed collagen fibrils next to osteoblasts, instead of the loosely arranged fibrils of normal osteoid. A low-phosphorus diet partly restores fibril organization. Reason: Direct ultrastructural evidence that a structurally abnormal alpha1(I) chain alters the organization of the fibrils it builds. Supporting Evidence: PMID:35282456 In contrast, the Chi/+ bone matrix is characterised by densely packed collagen fibrils in the vicinity of the osteoblasts (Figure 7C). |
| GO:0030278 regulation of ossification | IMP PMID:14623232 Radiographic analysis of zebrafish skeletal defects. | MODIFY | Summary: Original description of chihuahua (dc124), a dominant col1a1a mutation found by radiographic screening, which causes a general defect in bone growth resembling osteogenesis imperfecta. Abstract only. Reason: The mutant phenotype (a general defect in bone growth) supports a role for col1a1a in ossification. But the alpha1(I) chain acts as the structural organic matrix of bone, not as a regulator that modulates the rate or extent of ossification. The regulatory term implies a mechanism the evidence does not show. Replace with the parent process, ossification, keeping the acts_upstream_of_or_within qualifier. Proposed replacements: ossification Supporting Evidence: PMID:14623232 We have isolated chihuahua, a dominant mutation causing a general defect in bone growth. PMID:14623232 Mapping and molecular characterization of the chihuahua mutation indicates that the defect resides in the gene encoding the collagen I(alpha1) chain. |
| GO:0030282 bone mineralization | IMP PMID:35282456 Compression Fractures and Partial Phenotype Rescue With a Lo... | KEEP AS NON CORE | Summary: Chihuahua bone is overmineralized. Reducing dietary phosphorus lowers mineral content and partly rescues the phenotype. Reason: Collagen I fibrils are the template on which bone mineral is deposited, and an abnormal chain alters mineralization. This is a real but downstream consequence of the structural function, so it is kept as non-core. Supporting Evidence: PMID:35282456 Altered collagen structure and excess mineralisation are the main causes for the bone phenotype. |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Deep collagen-family IBA for extracellular matrix, the site of action of all collagen chains. Reason: Correct and appropriately specific. Type I collagen is extracted from the matrix of zebrafish bone, skin and scales. Supporting Evidence: PMID:26876635 In conclusion, we provided a deep molecular and biochemical characterization of zebrafish collagen type I, the most abundant extracellular matrix protein in bone and skin. |
| GO:0031101 fin regeneration | IMP PMID:21420398 Actinotrichia collagens and their role in fin formation. | KEEP AS NON CORE | Summary: Chihuahua (col1a1a^dc124/+) shows aberrant actinotrichia and lepidotrichia during fin regeneration. Abstract only. Reason: Plausible and consistent with col1a1a being the type I collagen gene of actinotrichia-forming cells. It is a context-specific use of the structural function, so non-core. Deferred to the curator, who read the full text. Supporting Evidence: PMID:21420398 The col1a1 dominant mutant chihuahua showed aberrant phenotypes in both actinotrichia and lepidotrichia during fin development and regeneration. |
| GO:0033333 fin development | IMP PMID:9007245 Genetic analysis of fin formation in the zebrafish, Danio re... | ACCEPT | Summary: Genotype col1a1a^tt281/tt281 (ZFIN), a recessive allele from the Tuebingen large-scale screen for fin formation mutants (abstract only; the allele is not named in the abstract). Reason: Fin fold development is a copy-specific role of col1a1a. It is the only type I collagen gene expressed in the median fin fold and pectoral fin margin. Actinotrichia, the collagen fibres that support the fin fold, are absent in col1a1a knockout larvae and are thought to contain alpha1(I) homotrimers. This role is not shared with col1a1b, so it is accepted as part of the col1a1a-specific function. Deferred to the curator for the allele-level details. Supporting Evidence: PMID:9007245 Mutations in 11 genes lead to abnormal morphology or degeneration of both caudal and pectoral fin folds. PMID:30082390 Upon detailed examination of the finfold, these actinotrichia were found to be absent in col1a1aβ/β mutant larvae (Fig. 5D). |
| GO:0033334 fin morphogenesis | IMP PMID:21420398 Actinotrichia collagens and their role in fin formation. | ACCEPT | Summary: Chihuahua (col1a1a^dc124/+) has abnormal actinotrichia and lepidotrichia during fin development. col1a1a is expressed in actinotrichia-forming cells. Reason: The alpha1(I) chain is a structural component of actinotrichia, the fibres that shape the fin fold, so col1a1a contributes structure to fin morphogenesis. This is the copy-specific part of the col1a1a function. Supporting Evidence: PMID:21420398 Both col1a1a and col2a1b were found in actinotrichia forming cells. PMID:26876635 Interestingly, only col1a1a was shown to be expressed in the median fin fold and in the apical ectodermal ridge of the pectoral fin at 48, 72 and 96 hpf |
| GO:0033339 pectoral fin development | IMP PMID:21420398 Actinotrichia collagens and their role in fin formation. | KEEP AS NON CORE | Summary: Morpholino knockdown (MO2-col1a1a) disrupts actinotrichia and fin fold morphogenesis. Abstract only. Reason: Morphant-only evidence, but consistent with the germline knockout, whose larvae have frilly pectoral fin margins and lack actinotrichia. Kept as a more specific, non-core instance of the fin role. Supporting Evidence: PMID:21420398 Morpholino knockdown in zebrafish embryos demonstrated that the two collagens and lh1 are essential for actinotrichia and fin fold morphogenesis. PMID:30082390 Furthermore, the distal margins of the pectoral fins, and the finfold, were shown to be ruffled in these mutants |
| GO:0035630 bone mineralization involved in bone maturation | IMP PMID:29665086 Severely Impaired Bone Material Quality in Chihuahua Zebrafi... | KEEP AS NON CORE | Summary: Multiscale analysis of chihuahua bone shows a higher degree of mineralization and lower collagen and mineral maturity. Abstract only. Reason: A real downstream effect of an abnormal collagen template on mineral deposition. Non-core for a structural matrix protein. Deferred to the curator on the precise child term. Supporting Evidence: PMID:29665086 At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to wild-type zebrafish. |
| GO:0043588 skin development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from a node holding the COL1A1 and COL3A1 clade, based on mammalian skin phenotypes. Reason: col1a1a is expressed in the basal epidermis, and type I collagen is a major skin collagen in zebrafish. The structural contribution to dermal matrix supports inheriting the term, but no zebrafish skin phenotype has been reported for col1a1a, so it is non-core. Supporting Evidence: PMID:26876635 At every time point, expression of all three genes could be detected in the epidermis. |
| GO:0046849 bone remodeling | IMP PMID:29665086 Severely Impaired Bone Material Quality in Chihuahua Zebrafi... | KEEP AS NON CORE | Summary: Chihuahua bone quality study (abstract only). The abstract reports altered osteoblast morphology and osteocyte density but does not mention remodeling. Reason: The effect on remodeling is at best indirect: the abnormal collagen matrix is what osteoclasts and osteoblasts turn over, and col1a1a performs no step of resorption or reactive formation. The acts_upstream_of_or_within qualifier fits such an indirect effect, and the full text was not available, so the row is kept as non-core rather than removed. Supporting Evidence: PMID:29665086 The alterations in the cellular, compositional, and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties |
| GO:0046849 bone remodeling | IMP PMID:35282456 Compression Fractures and Partial Phenotype Rescue With a Lo... | KEEP AS NON CORE | Summary: Chihuahua vertebrae show compression fractures with repair and abundant osteoclast (TRAP) activity compared with wild type. Reason: The increased osteoclast activity is a response to fractures and to the abnormal matrix. It is an indirect consequence of the structural defect, not a step of remodeling performed by the collagen chain. Kept as non-core under the acts_upstream_of_or_within qualifier. Supporting Evidence: PMID:35282456 Both Chi/+ and Chi/+LP show abundant osteoclast activity compared to WT. |
| GO:0048705 skeletal system morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the COL1A1/COL3A1 node, based on mouse skeletal phenotypes. Reason: Consistent with the zebrafish mutant phenotypes: vertebral malformation and shorter vertebral bodies in chihuahua and in dmh13 and dmh14. The broader skeletal system development term already covers this role, so this one is kept as non-core. Supporting Evidence: PMID:28835471 Analysis by microcomputed tomography (ΞΌCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches |
| GO:0005584 collagen type I trimer | IDA PMID:26876635 Zebrafish Collagen Type I: Molecular and Biochemical Charact... | NEW | Summary: Proposed location. Mass spectrometry of pepsin-extracted type I collagen from 48 hpf embryos and from adult bone, skin and scales identifies alpha1(I) peptides together with alpha3(I) and alpha2(I). Amino acid analysis excludes significant homotrimers in adult tissues and supports about equal amounts of the three chains. Reason: This is the complex the alpha1(I) chain is a subunit of. Human COL1A1 carries GO:0005584 by IDA/IPI/IMP. By definition the term covers both heterotrimers and alpha1(I) homotrimers, which also fits the proposed homotrimers in actinotrichia. The same term is proposed for col1a1b. Supporting Evidence: PMID:26876635 We demonstrated that, both in zebrafish embryos and adult tissues, three instead of two types of alpha chains contribute to the formation of the collagen type I triple helix PMID:26876635 a 1:1:1 ratio for the three Ξ± chains in all tissues is inferred |
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Download this section (compressed HTML)Q: ZFIN attaches two col1a1a skeletal system development IMP rows (PMID:30082390) to genotypes that carry no col1a1a allele (col1a1b^dmh29/+ and col1a2^dmh15/+). Should these rows move to col1a1b and col1a2? col1a1b currently has no annotation from PMID:30082390 at all.
Q: Is col1a1b (alpha3(I)) upregulated in col1a1a heterozygous nonsense mutants (transcriptional adaptation)? This would help explain why col1a1a+/- fish have no skeletal phenotype.
Q: Do actinotrichia really contain alpha1(I) homotrimers? The inference rests on in situ expression and co-migration, not on direct chain analysis of isolated actinotrichia.
Experiment: Chain-specific proteomics (SRM with alpha1(I)- and alpha3(I)-unique peptides) of isolated actinotrichia and of adult bone, skin and scale collagen from col1a1a+/- and col1a1b-/- fish, to measure trimer composition and any compensatory change in the other chain.
Type: targeted mass spectrometry
Experiment: Compare col1a1a nonsense (NMD) alleles with a promoter-deletion (RNA-less) col1a1a allele and quantify col1a1b expression, to separate transcriptional adaptation from true redundancy.
Type: genetic loss-of-function comparison
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