Role of PCDH12 in neural circuit formation during brain development and disease

The human brain contains billions of axons that follow precise pathways essential for the establishment of functional connections. Despite intensive efforts, only few disorders resulting from errors in axon guidance have been identified wherein, their molecular etiologies have not been elucidated. I have identified mutations in PCDH12 in families presenting abnormalities in brain connectivity. Identifying genetic causes will not only shed light on the pathological mechanisms but also will provide insight about the cellular and molecular machinery during development. A major challenge for understanding neurodevelopmental disorders to date, has been the lack of affected tissue. The capacity to differentiate neural tissue from patient induced pluripotent stem cells (iPSCs) opens an exciting avenue to reveal unique human features of disease. Thus, I will conduct mechanistic studies to characterize the functional interaction between PCDH12 and Cofilin pertaining to axon guidance in both iPSC and mouse disease models. To pursue the proposed research, I have proposed the following aims: Specific Aim 1: Characterize PCDH12-cofilin interaction in the disease model from iPSCs. Aim 1a: Identify the role of cofilin activity in axonal defects present in iPSCs with PCDH12 mutations. Aim 1b: Characterize the mechanism of PCDH12-cofilin interaction during axon growth. Specific Aim 2: Elucidate the mechanism by which Pcdh12-cofilin interaction influences circuit formation. Aim 2a: Characterize potential axonal tract defects/mechanisms in Emx1|cofilin conditional knockout mice. Aim 2b: Characterize the role of cofilin activity in axon growth in vivo.