Divya Alley

The L1 family of cell adhesion molecules (L1CAMs) are highly conserved immunoglobulin-like transmembrane molecules with well-studied functions in neuronal development. In humans, L1CAM mutations are associated with several neurological disorders, including L1 syndrome. Modifier genes likely contribute to the manifestation and severity of L1CAM disorders, but identifying these interacting genes in mammals has been challenging. Our lab uses the simple genetic model organism, C. elegans, to study the L1CAM ortholog encoded by the sax-7 gene. The SAX-7 protein is a model for human L1CAMs because it has conserved structural features and neuronal functions of mammalian L1CAMs. Previous research revealed an interaction between sax-7 and let-60 that encodes the Ras GTPase, an activator in the Ras Map Kinase (RMK) signaling pathway that is essential for C. elegans vulval development. While Ras null function exhibits a vulvaless phenotype (Vul), gain of Ras (let-60(gf)) leads to the multiple vulvae (Muv) phenotype. While sax-7 null (sax-7(0)) does not cause significant vulval abnormalities, sax-7(0) results in a significant increase let-60(gf) Muv phenotype severity, suggesting that sax-7 serves as a negative regulator for the RMK pathway. To test this hypothesis, we assessed for a genetic interaction between sax-7 and let-23 that encodes an EGF receptor. LET-23 activation results in Ras activation and is necessary for vulval development; let-23 null (let-23(0)) animals exhibit a Vul phenotype. We examined vulval development in sax-7(0); let-23(0) double mutants compared to let-23(0) animals. If our hypothesis is correct, sax-7(0) is expected to circumvent impaired let-23 function, suppressing the let-23(0) Vul phenotype.