The molecular mechanisms mediating axonal guidance: characterization of proteins linking Integrin and Plexin receptors in navigating axons

Axons simultaneously encounter multiple guidance cues as they navigate to their targets, but how these different signals are integrated to direct precise steering events is poorly understood. One of our interests is to better characterize a new family of unusual proteins, the MICALs, that play a critical role in transducing the intracellular axon guidance effects of one of the largest families of axon guidance cues, the semaphorins and their plexin receptors. One MICAL interacting protein that was recently identified is the SH3 domain containing protein Cas. Cas proteins stimulate actin filament assembly and integrin‐dependent cell migration in non‐neuronal cells and we have recently found that Cas works together with integrins to direct axon guidance. In the present study, we find that semaphorins and integrins exhibit antagonistic effects on navigating axons that are dependent upon MICAL and Cas. Cas and MICAL proteins are co‐localized in axons and MICAL controls the effectiveness of Cas to mediate axonal guidance. We also find that the regions of MICAL and Cas which facilitate binding are critical for their axon guidance functions. These results reveal a convergence of axon guidance signaling cascades at MICAL and Cas such that plexins signal the repulsion of axons through MICAL and the simultaneous modulation of integrin‐Cas adhesive/permissive axon guidance. Supported by NIH MH069787.