The proposed studies will identify mechanisms through which Cas adaptor proteins regulate cortical development and function. Accurate cell migration and lamination are indispensable for the development of a functional nervous system. Congenital disruption of any of these processes can result in neurodevelopmental disorders ranging from lissencephaly to autism-spectrum disorders. During multiple developmental steps, neurons are guided by repulsive and attractive cues, while actively interacting with the extracellular matrix (ECM) and other cells. Although much is known about the ligand-receptor pairs required for these cues to regulate cell trajectories, it remains unknown how instructive and adhesive cues are integrated and interpreted within the neuron. The Cas (Crk associated substrate) family of cytosolic adaptor proteins are known to signal downstream of several neural guidance cues, and regulate focal adhesion turnover. Using Cas proteins as a model, we have a unique opportunity to broaden our understanding of how instructive and permissive signaling pathways converge during neural development to regulate cell adhesion. To test the hypothesis that Cas proteins are essential for coordinating cortical lamination and migration, experiments will be organized into three Specific Aims. Guided by strong preliminary data showing that ablation of Cas genes results in cortical defects that resemble cobblestone lissencephaly, Aim 1 will establish, for the first time, the functional requirement for Cas proteins during cortical migration and lamination.
Aim 2 will explore the contributions of Cas-mediated cortical scaffold formation to physiology and behavior, using EEG and behavioral approaches.
Aim 3 will test how regulation of Cas function affects cortical lamination. These experiments will provide new knowledge on the basic mechanisms underlying the establishment of neural circuits essential for perception and cognition.
The project is relevant to public health and NIH's mission, as mutations in Cas genes result in severe cortical dysplasia. The proposed research pursues fundamental knowledge of the molecular mechanisms of neural circuit assembly and their contributions to normal brain physiology, which will provide a foundation to understand the etiology of neurodevelopmental disorders.
