The formation of the mammalian neocortex is a complicated process requiring the coordination of neurogenesis and the migration postmitotic neuronal precursors. The radial glia stem cells undergoing neurogenesis oscillate their nuclei in synchrony with cell cycle progression in a process known as interkinetic nuclear migration (INM). After this, progeny migrate along the basal processes of the radial glia to their final location in the cerebral cortex. The major microtubule minus-end directed motor protein dynein has been shown to be crucial for both of these processes INM and postmitotic migration, particularly for movement of the nucleus. Dynein depends on a variety of adaptor proteins to enhance its functionality, and recent work from our lab has shown the investigated the unique and overlapping roles of the paralog proteins NudE and NudEL (arising from the NDE1 and NDEL1 genes respectively). Both proteins are known to undergo a variety of posttranslational modifications, and phosphorylations of the proteins are known to greatly impact their function. Importantly our lab has shown that Cdk1 phosphorylation of proteins in radial glia control apical INM, and NudE is a known substrate of Cdk1. Additionally, mutations in the human NDE1 gene have been linked to severe forms of microcephaly as well as multiple cases of schizophrenia. It is fascinating that these two diseases, which are on opposing ends of the clinical spectrum in many aspects, can arise from mutations in different regions of the same protein. The goals of this project are to: determine the effects of phosphorylation site mutations and microcephaly-causing NDE1 mutations on radial glia function in the developing rat neocortex (Aim 1), and investigate the role of NudE and NudEL during the postmitotic precursors and the effect of the schizophrenia-causing mutations of NDE1 on postmitotic neuronal migration. Using in utero electroporation of NudE with a variety of site-directed mutations to impair phosphorylation or mimic the human mutations, further insight can be gained into the pathophysiology of microcephaly and schizophrenia during neocortical development.

Public Health Relevance

Formation of the neocortex is one of the most complicated processes in mammalian neurodevelopment, involving the coordination of neurogenesis and postmitotic neuronal migration. NudE, a dynein-adaptor protein, is involved in both neurogenesis and postmitotic migration, and is known to cause microcephaly in humans and be associated with schizophrenia. This project seeks to use highly sophisticated cell biological approaches in the developing rat neocortex to examine how these specific mutations - as well as similar mutations to phosphorylation sites - may contribute to the pathology of such dramatically different neuropsychiatric disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NST-2 Subcommittee (NST)
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Riddle, Robert D
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Doobin, David J; Dantas, Tiago J; Vallee, Richard B (2017) Microcephaly as a cell cycle disease. Cell Cycle 16:247-248
Rosenfeld, Amy B; Doobin, David J; Warren, Audrey L et al. (2017) Replication of early and recent Zika virus isolates throughout mouse brain development. Proc Natl Acad Sci U S A 114:12273-12278
Doobin, David J; Kemal, Shahrnaz; Dantas, Tiago J et al. (2016) Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages. Nat Commun 7:12551