Functional Role for Cas Cytoplasmic Adaptor Proteins During Cortical Axon Pathfinding

Proper neural circuit organization requires individual neurons to project to their targets with high specificity. While several guidance molecules have been shown to mediate axonal fasciculation and pathfinding, less is understood about how neurons intracellularly interpret and integrate these cues. Here we provide genetic evidence that the Crk-Associated Substrate (Cas) family of intracellular adaptor proteins is required for proper fasciculation and guidance of two cortical white matter tracts: the Anterior Commissure (AC) and thalamocortical axons (TCAs). Using a Cas Triple Conditional Knock Out ( Cas TcKO ) mouse model, we show that Cas proteins are required non-neuronally for TCA projections in a manner that phenocopies the non-neuronal requirement for the β1-integrin receptor. Additional analysis of Cas TcKO mutants reveals a neuronal-autonomous role in AC fasciculation that is not phenocopied in β1-integrin deficient mutants, suggesting that Cas proteins might signal downstream of a different receptor during this axon pathfinding event. These findings implicate Cas proteins as key mediators of cortical axon tract fasciculation and guidance.