Malformations of cortical development (MCD) represent a major cause of developmental disabilities and are at the root of numerous neurological disorders. Although human genetic studies have established a link between a class of centrosome proteins and MCD, the in vivo functions of these proteins and the pathophysiological mechanisms of MCD diseases remain obscure. Focusing on one MCD disease-associated gene Wdr62, which encodes a centrosome protein, the goals of this proposal are to determine the in vivo roles and functional mechanisms of Wdr62 during normal cortical development and to investigate how Wdr62 mutations lead to a wide spectrum of MCD disorders.
Three specific aims are proposed over the next 5 years. The first is to use mouse genetic approaches to determine the developmental and cellular functions of Wdr62 in normal cortical development. The second is to test the in vitro and in vivo roles of individual Wdr62 disease-associated mutations during cortical development. My last aim is to develop a new affinity purification method to identify the regulators that mediate WDR62 functions from developing mouse brains. These studies will advance the field not only by providing novel insights into the physiological functions and mechanisms of action of Wdr62, but also by contributing fundamental knowledge to elucidate the etiologies of MCD diseases.
Improved understanding of normal cortical development and malformations of cortical development (MCD), which is the focus of this proposal, is critical to medical management for people suffering from related neurological disorders.
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