samsn1a (SAM domain, SH3 domain and nuclear localization signals 1a) is one of two zebrafish co-orthologs of vertebrate SAMSN1 (HACS1, SLy2, NASH1); its paralog is samsn1b. It encodes an intracellular adaptor of the SLy/SASH1 family with an N-terminal disordered region, a central SH3 domain and a C-terminal SAM domain. In mammals SAMSN1 is expressed mainly in hematopoietic cells, is found in cytoplasm and nucleus, is induced by B-cell activation signals, binds tyrosine-phosphorylated proteins and, through its SH3 domain, the inhibitory receptor PIRB, and acts as an inhibitory adaptor that dampens B-cell activation (mouse knockout B cells are hyper-responsive). The zebrafish protein keeps a highly conserved SH3 domain but is much longer than human SAMSN1 and only 38% identical to samsn1b overall. samsn1a is zygotically expressed; in situ hybridization detects it in blood and macrophages of the early embryo, bulk RNA-seq places it highest in granulocytes, spleen and head kidney, and single-cell studies use it as a marker of retinal bipolar cells. No functional study of the zebrafish gene has been published.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0050869 negative regulation of B cell activation | IBA GO_REF:0000033 | ACCEPT | Summary: Negative regulation of B cell activation, propagated from the SAMSN1 node PTN002642349, whose experimental seed is the mouse Hacs1 (Samsn1) knockout. Reason: The IBA places the function at a node that contains both zebrafish SAMSN1 co-orthologs. The seed evidence is sound (Hacs1-/- B cells hyper-proliferate on BCR stimulation and show increased tyrosine phosphorylation), and the SH3 domain that mediates the PIRB interaction is 82% identical between samsn1a and human SAMSN1. samsn1a is expressed in blood, macrophages, granulocytes, spleen and head kidney, so there is no expression-based argument that it sits outside immune cells. The function has not been tested in zebrafish; the annotation is accepted as a phylogenetic inference, and the same call is made for samsn1b. Supporting Evidence: PMID:19923443 Purified splenic B cells from Hacs1(-/-) mice showed increased cell proliferation on BCR (B-cell receptor) stimulation. PMID:19923443 This study suggests that Hacs1 is an immunoinhibitory adaptor that might be a useful target for immune suppression therapy. file:DANRE/samsn1a/samsn1a-bioinformatics/RESULTS.md The SH3 domain is the best-conserved part of both copies |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of intracellular signal transduction, propagated from the SLy/SASH1 family node PTN000266438 (seeded by human SASH1). Reason: A broad but appropriate process for an SH3-SAM adaptor of the SLy/SASH1 family. The mammalian family members act as intracellular signalling adaptors, and SAMSN1 itself associates with tyrosine-phosphorylated proteins after B-cell receptor stimulation. samsn1a keeps the SH3 and SAM domains that define the family. The term is general, but no more specific process is established across the family. Supporting Evidence: PMID:33710696 Intracellular adaptor proteins are indispensable for the transduction of receptor-derived signals, as they recruit and connect essential downstream effectors. PMID:15381729 HACS1 associates with tyrosine-phosphorylated proteins after B cell activation and binds in vitro to the inhibitory molecule paired Ig-like receptor B. |
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Download this section (compressed HTML)Q: Which zebrafish blood cell types express samsn1a and samsn1b (macrophages, neutrophils, B cells, dendritic-like cells), and do the two copies overlap in any of them?
Q: Is the retinal expression split between the copies (samsn1a in bipolar cells, samsn1b in photoreceptors and pineal) a zebrafish-specific partition, and is gar SAMSN1 expressed in retina?
Q: Does the long N-terminal region shared by the fish and gar proteins but absent from human SAMSN1 carry functional motifs (for example 14-3-3 or phosphotyrosine docking sites)?
Experiment: Generate samsn1a mutants (ideally promoter-less or RNA-less alleles to avoid transcriptional adaptation) alone and with samsn1b; measure adult B-cell responses to immunization and larval macrophage and neutrophil responses to infection or wounding.
Hypothesis: samsn1a restrains activation of zebrafish B cells or myeloid cells, as Hacs1 does in mouse.
Type: genetic interaction
Experiment: Double fluorescent in situ (HCR) or reanalysis of zebrafish single-cell atlases for the two copies in blood, kidney marrow, retina and pineal, with gar SAMSN1 as an outgroup.
Hypothesis: samsn1a and samsn1b have complementary cell-type expression.
Type: expression analysis
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