Body size in C. elegans is regulated by a TGF-beta-like signaling pathway that controls both animal length (Sma) and male tail development (Mab). The Sma/Mab pathway is activated when its ligand, DBL-1, binds to a heteromeric complex of transmembrane receptor serine kinases (RSKs), DAF-4 and SMA-6, resulting in phosphorylation and nuclear accumulation of transcriptional regulators known as Smads, SMA-2, SMA-3, and SMA-4. While the ligand DBL-1 is expressed in nerve cells, the focus of this pathway appears to act in the hypodermis, where the receptors and Smads are required. We isolated five alleles of
sma-10 in a screen to identify novel members of this pathway. Mutant animals range in size from 60 to 75% the length of wild-type worms. Genetic analyses indicate that it functions between
dbl-1 (ligand) and
sma-6 (receptor), suggesting that SMA-10 may function at the cell surface, upstream of SMA-6. To further elucidate its molecular function, we have cloned
sma-10 using SNP mapping and germline transformation rescue.
sma-10 encodes a protein with several leucine-rich repeats, 3 IG-like domains, a single transmembrane domain, and an intracellular domain of only 19 amino acids. This structure suggests that SMA-10 and its homologs may function as extracellular cell-surface binding proteins for TGF-beta-related ligands or receptors. Predicted proteins with significant similarity to SMA-10 have been identified in animal genomes from fly to human, but none of these provides any additional insight into the possible function of SMA-10. The Drosophila gene rescues the phenotype of
sma-10(lf) . Notably, the gene for a closely related human protein has been mapped to a region that is deleted in several tumor lines, similar to other members of TGF signaling pathways that function as tumor suppressors. The rescuing translational fusion
sma-10p::
sma-10:gfp fluoresces brightly in the pharynx and weakly in the hypodermis. However, rescue of the body size defect is achieved with a hypodermal promoter. From these results, we propose that SMA-10 is a novel, conserved positive regulator of TGF-beta signaling.