DBL-1 BMP-like Sma/Mab signaling in Caenorhabditis elegans body size control

In Caenorhabditis elegans the BMP2/4-related ligand DBL-1 is secreted mainly by neurons and acts on the epidermis (hypodermis) to promote postembryonic growth and to pattern the male tail. DBL-1 signals through a receptor pair of the type I serine/threonine kinase SMA-6 and the type II kinase DAF-4, and then through the Smads SMA-2 and SMA-3 together with the co-Smad SMA-4. Loss of any of these components gives small (Sma) animals with abnormal male tails (Mab), and the DBL-1 dose sets body length, so overexpression makes animals longer. SMA-3 is the principal receptor-regulated Smad. Signaling is tuned at the cell surface: the glypican LON-2 restrains it, apparently through the matricellular protein SMOC-1, which binds both LON-2 and DBL-1, rather than by binding DBL-1 directly; and the LRIG-family transmembrane protein SMA-10, which binds both receptors and supports SMA-6 endocytic trafficking, enhances it. In the nucleus the Schnurri-family zinc finger protein SMA-9 acts as a transcriptional cofactor that mainly represses targets in body size control. One downstream target is lon-1, which encodes a secreted CAP/CRISP-family protein made in the hypodermis. The pathway represses lon-1, and LON-1 limits body size, binds sterol in vitro and feeds back to dampen pathway output. The same ligand, receptors and SMA-3 also act in epidermal antifungal defense, lipid storage and other outputs.

Boundary. A concrete C. elegans module for the DBL-1 (Sma/Mab) BMP-like pathway in body size control. Root parts: the DBL-1 ligand; two cell-surface modulators (LON-2 glypican, negative; SMA-10 LRIG, positive); the SMA-6/DAF-4 receptor pair; the SMA-2/SMA-3/SMA-4 Smads; the SMA-9 cofactor; and the repressed body-size target LON-1. Male tail ray patterning uses the same core and is recorded in prose only. Other outputs that share the ligand and receptors are outside this boundary: epidermal antifungal caenacin induction (PMID:19198592, modeled in GO-CAM gomodel:5b91dbd100002241), lipid storage via insulin signaling (PMID:29162682), and the SMA-3 branch of molting AMP induction noted in MODULE:c_elegans_jak_independent_stat_signaling. Other positive regulators of the pathway (the RGM protein DRAG-1, the tetraspanins TSP-12/TSP-14 with SUP-17, and UNC-40) are not modeled. Excluded member. LON-8 was checked and is excluded. Its gene review and the primary paper (PMID:17374156) show that it regulates body size and male ray morphology independently of the Sma/Mab pathway, and that its mRNA is not changed in dbl-1 or sma-6 mutants, unlike lon-1. Relation to generic modules. MODULE:bmp_signaling and MODULE:tgfb_smad_signaling describe ligand-receptor engagement, type I receptor phosphorylation of receptor Smads, and Smad transcriptional output. This worm module follows that trunk. DAF-4 is the type II receptor shared with the DAF-7 dauer pathway, and SMA-6 is the type I receptor specific to this pathway. Receptor phosphorylation of SMA-2/SMA-3 is inferred from the conserved mechanism and is not directly evidenced in the sources used here. A Schnurri cofactor (SMA-9) and extracellular modulators are added. Grounding. DBL-1 G5EEL5 comes from its gene review. The other accessions come from UniProt REST (organism 6239): SMA-6 Q09488, DAF-4 P50488, SMA-2 Q02330, SMA-3 P45896, SMA-4 P45897, SMA-9 Q7JM44, LON-1 Q09566 and SMA-10 Q965M2 (all Swiss-Prot), and LON-2 Q18530 (TrEMBL; the only lon-2 entry). Every grounded protein has a gene review, and each annoton MF follows the core_functions of that review. SMA-6 and DAF-4 use BMP receptor activity (GO:0098821, a child of GO:0004675). DAF-4 also has transforming growth factor beta receptor activity with DAF-1 in the DAF-7 dauer pathway, which is outside this module. SMA-2, SMA-3 and SMA-4 use RNA polymerase II-specific DNA-binding transcription factor activity. SMA-10 uses type I TGF-beta receptor binding; its review also records type II receptor binding (GO:0005114, to DAF-4). SMA-9 uses transcription corepressor activity, matching its main role in body size; its review also records coactivator activity in male tail patterning and an antagonistic, opposite-sign role in M-lineage dorsoventral patterning. LON-1 uses sterol binding, shown only in vitro. LON-2 is modeled with no MF, following its review: an earlier draft gave growth factor binding (GO:0019838) from BMP2 binding in vitro, but worm LON-2 did not bind DBL-1 in co-IP, and SMOC-1 bridges the two (PMID:37590248). SMOC-1 has no gene review and is not modeled as a part.