The formation of appropriate neural connectivity depends on neuronal placement in the developing brain. Appropriate neuronal placement, the basis for the emergence of neuronal connectome or wiring, is achieved through a process of coordinated pattern of neurogenesis and neuronal migration, enabling distinct classes of neurons to navigate from their sites of birth to their final laminar and areal destinations in the cerebral cortex. Radial glial progenitors in the developing cerebral cortex support neurogenesis and neuronal migration. Disruptions in radial progenitor development and neuronal migration, resulting from genetic mutations or environmental insults, alter the positioning and thus the connectivity and function of cortical neurons. Area specific and neuronal type specific defects in neuronal placement and the resultant changes in neuronal connectivity is an underlying cause of a wide spectrum of neurological disorders, including autism, schizophrenia, epilepsy, fetal alcohol syndrome, and malformations such as lissencephaly, schizencephaly, microencephaly, and macro/microgyria.
Our goal is to understand the following four inter-related processes essential for the formation of functional neural circuitry in the cerebral cortex: (1) What are the signals that regulate the establishment, development and differentiation of radial glial cells, a key substrate for neurogenesis and neuronal migration in cerebral cortex?, (2) how do different types of cortical neurons (i.e., projection neurons and interneurons) migrate at the right time in right numbers to appropriate cortical areas?, (3) what are the cellular mechanisms that guide the navigation and placement of distinct classes of cortical neurons?, and (4) how do different neurons elaborate their distinct architecture necessary for the formation of functional circuitry? These studies provide a framework to characterize the neuron-glial mechanisms essential for the emergence of cerebral cortical organization. An understanding of these mechanisms and how they are altered in models of neurodevelopmental disorders will help to delineate the pathophysiological processes that culminate in neurodevelopmental disorders.
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