FEM-3 is a terminal sex-determination regulator that promotes male cell fate in the nematode Caenorhabditis briggsae. In XO animals it directs male somatic differentiation in all tissues, and in XX hermaphrodites it specifies the early germ cells to adopt the sperm fate before the switch to oogenesis. FEM-3 acts together with FEM-1 and FEM-2 as a substrate-recognition module of a CUL-2 (Cullin-2) RING E3 ubiquitin-ligase complex that ubiquitinates the transcription factor TRA-1 (the Gli-family terminal repressor of male development), targeting it for proteasomal degradation; loss of FEM activity leaves TRA-1 active and feminizes the animal. FEM-3 activity is antagonized upstream by the membrane receptor TRA-2, which binds FEM-3 directly to repress its male-promoting function. The FEM-3 protein is the most rapidly diverging protein known in Caenorhabditis, and its interaction surface with TRA-2 coevolves in a strictly species-specific manner, making the gene a notable example of rapid coevolution within a conserved developmental pathway.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-based (GO_REF:0000107) transfer from the C. elegans ortholog FEM-1/FEM-3 complex context. FEM proteins act as the cytoplasmic/peri-nuclear substrate-recognition module of the CUL-2 ligase that degrades TRA-1; a cytoplasmic location is consistent with this role but is a broad cellular-component term and not the core function. |
| GO:0007530 sex determination | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Correct but high-level parent of the gene's specific role. The experimentally supported and more informative term is male sex determination (GO:0030238)/male somatic sex determination (GO:0019102); this general term is retained as non-core. |
| GO:0008287 protein serine/threonine phosphatase complex | IEA GO_REF:0000107 | REMOVE | Summary: Almost certainly an over-propagated electronic annotation. FEM-2 is the PP2C-type protein serine/threonine phosphatase of the FEM module; FEM-3 itself is not a phosphatase and there is no evidence it is a structural part of a phosphatase complex. The biologically relevant complex for FEM-3 is the CUL-2 RING E3 ubiquitin-ligase complex (GO:0031462). This term appears to result from transfer of an interactor's (FEM-2) annotation. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-general and mechanistically indirect. FEM-3 promotes degradation of the TRA-1 transcriptional repressor, which derepresses male target genes, but FEM-3 is not itself a transcriptional regulator; the downstream gene-expression effect is a consequence of proteolytic regulation of TRA-1. Best captured by the male sex-determination process terms rather than by a generic positive-regulation-of-gene-expression term. |
| GO:0019102 male somatic sex determination | IEA GO_REF:0000107 | ACCEPT | Summary: Consistent with the orthologous family and independently supported experimentally in C. briggsae (see the IMP annotation from PMID:12477393). FEM-3 directs male somatic differentiation in all tissues of XO animals. Core process. |
| GO:0019903 protein phosphatase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reflects the documented physical interaction between FEM-3 and the PP2C phosphatase FEM-2 within the FEM module (transferred from the C. elegans ortholog). This is a genuine binding partner, but the binding is in service of assembling the substrate-recognition module of the CUL-2 ligase; it is a supporting molecular interaction rather than the core molecular function. Retained as non-core. |
| GO:0030238 male sex determination | IEA GO_REF:0000107 | ACCEPT | Summary: Accurate and central to FEM-3 function; FEM-3 is a male-promoting (masculinizing) gene whose loss feminizes the animal. Supported both by orthology and by the C. briggsae RNAi/epistasis data in PMID:12477393. Core process. |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Correct and biologically central. FEM-3 (with FEM-1 and FEM-2) is part of the CUL-2-based RING E3 ubiquitin-ligase complex (CUL-2/ELC-1/RBX/FEM-1/FEM-2/FEM-3) that ubiquitinates TRA-1. This is the defining complex for the gene's molecular role. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: True but uninformative root-level complex term; subsumed by the specific Cul2-RING ubiquitin ligase complex (GO:0031462) annotation. Retained as non-core. |
| GO:0042006 masculinization of hermaphroditic germ-line | IEA GO_REF:0000107 | ACCEPT | Summary: Strongly supported by the biology: in XX hermaphrodites FEM-3 specifies the first germ cells to become sperm (the transient spermatogenic program), a masculinization of the hermaphrodite germ line. Consistent with the C. elegans ortholog and with the conserved fem-3 function shown in PMID:12477393. Core germline aspect of the male-promoting role. |
| GO:0060282 positive regulation of oocyte development | IEA GO_REF:0000107 | REMOVE | Summary: Directionally wrong, not merely over-general. FEM-3 promotes the sperm fate and is antagonistic to oogenesis; gain-of-function fem-3 alleles in C. elegans cause excess sperm and failure of the sperm-to-oocyte switch (masculinized germ line), i.e. they suppress, not promote, oocyte development. The positive-regulation directionality contradicts FEM-3's established germline role and should be removed rather than retained as over-general. |
| GO:0071168 protein localization to chromatin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: No support for a direct chromatin-localization role for FEM-3. FEM-3 acts in the cytoplasm as a ubiquitin-ligase substrate-recognition component; any effect on a chromatin-associated factor (TRA-1) is via proteolysis, not by mediating its localization to chromatin. Likely an over-propagated electronic annotation. |
| GO:1904146 positive regulation of meiotic cell cycle process involved in oocyte maturation | IEA GO_REF:0000107 | REMOVE | Summary: Directionally wrong and not supported by FEM-3's established role; FEM-3 promotes spermatogenesis and antagonizes oocyte/oogenesis programs rather than positively regulating oocyte meiotic maturation. The positive-regulation directionality contradicts FEM-3 biology and should be removed. |
| GO:1905936 regulation of germ cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Not a recognized core function of FEM-3, which acts in germline sex (fate) determination rather than in regulating germ cell proliferation per se. Plausibly a peripheral/indirect effect at most; treated as non-core given the weak (electronic, orthology-transferred) evidence. |
| GO:0005515 protein binding | IPI PMID:12477393 Rapid coevolution of the nematode sex-determining genes fem-... | MARK AS OVER ANNOTATED | Summary: Experimentally supported physical interaction (IPI; WITH UniProtKB:Q17307, C. briggsae TRA-2): Haag et al. showed FEM-3 binds TRA-2 in a strictly species-specific manner. The binding itself is real and important, but the bare 'protein binding' term is uninformative. The interaction underlies FEM-3's role as a substrate-recognition/adaptor component; the specific function is better expressed by the ubiquitin ligase-substrate adaptor activity captured in core_functions. Proposed replacements: ubiquitin ligase-substrate adaptor activity |
| GO:0019102 male somatic sex determination | IMP PMID:12477393 Rapid coevolution of the nematode sex-determining genes fem-... | ACCEPT | Summary: Experimentally supported in C. briggsae by RNAi (IMP): Haag et al. used RNA interference to show that the male-promoting function of fem-3 and its epistatic relationship with the upstream repressor tra-2 are conserved across C. elegans, C. briggsae and C. remanei. This is the strongest, species-specific evidence for FEM-3's core role and should be retained. |
| GO:1990756 ubiquitin ligase-substrate adaptor activity | ISS GO_REF:0000024 | NEW | Summary: Proposed molecular-function annotation capturing FEM-3's role as a substrate-recognition/adaptor component of the CUL-2 RING E3 ubiquitin-ligase complex that targets TRA-1 for ubiquitination (with FEM-1 and FEM-2). This is the informative MF replacement for the bare 'protein binding' (IPI) annotation and is supported by orthology to C. elegans FEM-3 and by the established CUL-2/FEM degradation machinery for TRA-1. |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)