UC Riverside

Laminar organization of the cortex requires neurons to exit the cell cycle, locomote, and assemble into six distinct layers. Neurons encounter multiple permissive and repulsive guidance cues simultaneously during cell migration. The molecular mechanism of how these cues are interpreted by migrating cells is not well understood. To gain insight into the mechanisms of signal transduction that participate during cortical migration and lamination, we studied the three embryonically-expressed Cas signaling adaptor proteins (p130Cas, CasL, and Sin) to uncover the signaling events essential cortical development. We hypothesize that the Cas family of proteins mediate adhesion signal transduction during corticogenesis as they are known to mediate integrin-dependent signals at focal adhesion complexes. Here, we provide in vivo genetic evidence that Cas proteins serve a functional and redundant role during cortical lamination. Cas triple conditional knock-out (CasTcKO) mice display severe cortical phenotypes that resemble cobblestone lissencephaly. The malformation in CasTcKO brains include ectopic clusters of neurons in the marginal zone and meninges. Furthermore, all excitatory neuronal subpopulations are disrupted in CasTcKO mutants. Defects in neuronal positioning appear to be non-neuronal autonomous, suggesting that Cas genes are required in radial glial cells for proper cortical lamination. Disruption to radial glial interactions with the basement membrane resulted in disarrayed radial glial basal processes and ectopic proliferating cells. Molecular epistasis analysis placed Dystroglycan, a known regulator of glial-pial interactions, upstream of Cas phosphorylation. Furthermore, this dystroglycan-dependent recruitment of phosphorylated Cas to radial glial endfeet requires β1 integrin signaling. Overall, our data support an essential role for Cas adaptor proteins during cortical lamination by acting downstream of dystroglycan and β1 integrin in radial glial cells.