The developing cerebral cortex is a sensitive target for genetic diseases and for gestational exposure to toxins, infection and radiation. Despite this, the basic cellular and molecular mechanisms of cortical development, particularly early cortical development are not well understood. Using a novel 3D cortical hemisphere explant approach and reporter mice, we will examine the cellular behaviors that initiate cortical plate formation and determine how the secreted ligand, Reelin coordinates these behaviors. We will focus on the role of Reelin-dependent modulation of the focal adhesion adaptor protein Paxillin that we find dynamically expressed during early cortical development and aberrantly expressed in reeler mice cortices that lack Reelin. We are using pharmacological and RNAi-based approaches to target downstream signaling elements in the Reelin signaling pathway to determine Reelin's and Paxillin's role(s) in triggering and/or sustaining this morphological differentiation and motility. These studies will help resolve competing models of Reelin function, while providing further molecular and cellular insights into the formation of a cellular layer of the cerebral cortex. Insight into Reelin's role in cortical development will provide a general insight into the development and organization of neurons throughout the central nervous system. In adults, Reelin is up regulated in epileptic foci, and in response to nerve injury. Reelin may therefore have additional important roles in healing and functional recovery.

Public Health Relevance

Brain malformations are increasingly appreciated as an underlying cause of certain forms of epilepsy, mental retardation, autism, dyslexia and reading disorders. This proposal examines molecular and cellular events that occur at an early stage of brain development, but that have a major impact on later brain function and cognition. The work will provide a framework for understanding the etiology of cerebral cortical malformations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Upstate Medical University
Other Basic Sciences
Schools of Medicine
United States
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Rashid, Mamunur; Belmont, Judson; Carpenter, David et al. (2017) Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation. Development 144:4002-4014
Goreczny, G J; Ouderkirk-Pecone, J L; Olson, E C et al. (2017) Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 36:2693-2703
O'Dell, Ryan S; Cameron, David A; Zipfel, Warren R et al. (2015) Reelin Prevents Apical Neurite Retraction during Terminal Translocation and Dendrite Initiation. J Neurosci 35:10659-74
Nichols, Anna J; O'Dell, Ryan S; Powrozek, Teresa A et al. (2013) Ex utero electroporation and whole hemisphere explants: a simple experimental method for studies of early cortical development. J Vis Exp :
Cameron, David A; Middleton, Frank A; Chenn, Anjen et al. (2012) Hierarchical clustering of gene expression patterns in the Eomes + lineage of excitatory neurons during early neocortical development. BMC Neurosci 13:90
O'Dell, Ryan S; Ustine, Candida J M; Cameron, David A et al. (2012) Layer 6 cortical neurons require Reelin-Dab1 signaling for cellular orientation, Golgi deployment, and directed neurite growth into the marginal zone. Neural Dev 7:25
Matsuki, Tohru; Matthews, Russell T; Cooper, Jonathan A et al. (2010) Reelin and stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143:826-36
Nichols, Anna J; Olson, Eric C (2010) Reelin promotes neuronal orientation and dendritogenesis during preplate splitting. Cereb Cortex 20:2213-23