The C. elegans L1CAM homologue LAD-2 functions as a coreceptor in MAB-20/Sema2–mediated axon guidance

Abstract

The L1 cell adhesion molecule (L1CAM) participates in neuronal development. Mutations in the human L1 gene can cause the neurological disorder CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). This study presents genetic data that shows that L1-like adhesion gene 2 (LAD-2), a Caenorhabditis elegans L1CAM, functions in axon pathfinding. In the SDQL neuron, LAD-2 mediates dorsal axon guidance via the secreted MAB-20/Sema2 and PLX-2 plexin receptor, the functions of which have largely been characterized in epidermal morphogenesis. We use targeted misexpression experiments to provide in vivo evidence that MAB-20/Sema2 acts as a repellent to SDQL. Coimmunoprecipitation assays reveal that MAB-20 weakly interacts with PLX-2; this interaction is increased in the presence of LAD-2, which can interact independently with MAB-20 and PLX-2. These results suggest that LAD-2 functions as a MAB-20 coreceptor to secure MAB-20 coupling to PLX-2. In vertebrates, L1 binds neuropilin1, the obligate receptor to the secreted Sema3A. However, invertebrates lack neuropilins. LAD-2 may thus function in the semaphorin complex by combining the roles of neuropilins and L1CAMs.

unc-44 Ankyrin and stn-2 γ-Syntrophin Regulate sax-7 L1CAM Function in Maintaining Neuronal Positioning in Caenorhabditis elegans

“…The SAX-7 cytoplasmic tail is required to maintain neuronal positioning: To investigate the role of the SAX-7 cytoplasmic tail (SAX-7CT) in neuronal positioning, we generated two constructs: (1) SAX-7DCTTGFP, where the cytoplasmic tail is removed and GFP is fused to the remaining SAX-7 sequence and (2) SAX-7DCTTLAD-2CT where the SAX-7 cytoplasmic tail is deleted and replaced by the divergent LAD-2 cytoplasmic tail, which lacks the intracellular motifs found in SAX-7 (Wang et al 2008). Transgenic sax-7(eq1) animals expressing either construct exhibited displaced GABAergic neurons, revealing that specific sequences in the SAX-7 cytoplasmic tail are required to mediate neuronal positioning.…”

“…lad-2 encodes an L1CAM with conserved ectodomains but a divergent cytoplasmic tail that does not share any sequence homology with vertebrate L1CAMs (Wang et al 2008). In contrast, the sax-7 gene encodes a canonical L1CAM that more closely resembles vertebrate L1CAMs; both the ectodomains and intracellular motifs present in vertebrate L1CAMs are conserved in the SAX-7 protein (Chen et al 2001;Sasakura et al 2005;Wang et al 2005).…”

Cellular Strategies of Axonal Pathfinding

“…These examples are not the norm as in the absence of single CAMs or ECM components, few defects are normally observed in neurons in axonal pathfinding or organization, such as in the loss of b integrin in a conditional knockout mouse (Schwander et al 2004). Further, these mutant phenotypes may not be explained by the loss of adhesive interactions per se, but instead may be ascribed to the proposed role of CAMs such as L1 or integrins as crucial accessory receptors involved in semaphorin signaling (Castellani et al 2000;Pasterkamp et al 2003;Bechara et al 2007;Wolman et al 2007;Law et al 2008;Wang et al 2008).…”

Amino- and carboxyl-terminal domains of Filamin-A interact with CRMP1 to mediate Sema3A signalling

“…The irregular frequency of plx-2(tm729) was milder than that of mab-20(ev574), suggesting the participation of another receptor component in Sema2a signalling, such as LAD-2 (ref. 42). As plx-2(tm729)-null mutant did not augment the DD/VD phenotype of fln-1(tm545)-null mutant (Fig.…”