the abstract): The cerebral cortex is affected in a range of neuropsychiatric disorders including the disruption of normal cortical development that results in autism, childhood schizophrenia and mental retardation. Understanding normal cerebral cortical development will improve the diagnostic and therapeutic options for these and related disorders. This application will add to our knowledge of how neurons arise during the embryonic formation of the cerebral cortex by exploring a new mechanism: lysophosphatidic acid (LPA) signaling through its first receptor called lysophospholipid A1 receptor (LPA1) or Ventricular zone gene-1 (Vvz-1). LPA is a bioactive lipid that has properties of an extracellular signaling molecule and growth factor in non-neural cell lines. This 5-year ISA/K02 application for salary support will thus test the hypothesis that LPA affects cortical development by influencing neurogenesis through its newly identified cognate receptor, LPA1. The hypothesis will be tested through 4 specific aims.
Aim 1 will determine embryonic developmental expression patterns of LPA1 by continuing in situ hybridization analyses, generating specific antisera and using these for immunohistochemical analyses of embryonic cortical development.
Aim 2 will determine effects of LPA in primary cortical cultures by employing several distinct primary culture techniques to examine real-time morphological changes, cytoskeletal changes, cell fates and whole-brain organization. These studies will define responses and effects of LPA signaling on embryonic cortical cells in culture.
Aim 3 will identify and characterize the function of members of a new lysophospholipid receptor gene family that are also expressed in embryonic cortex, and new genes from this family.
Aim 4 will produce and analyze mice lacking LPA1, a necessary approach to assessing biological relevance of LPA signaling in the intact animal, since no specific competitive antagonists are currently available.
These aims will provide insights into a new influence on the developing cerebral cortex, and can potentially open new avenues to the study and treatment of a range of neuropsychiatric disorders, through the functioning of this novel group of molecules, the bioactive lysophosopholipids and their cognate receptors.
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