Understanding the development of the cerebral cortex and the extracellular signals used by forming neurons has clear relevance to mental and neurological diseases. This proposal continues studies on a new extracellular signaling system that was discovered in prior supported work on the cortex.The simple phospholipid called """"""""lysophosphatidic acid"""""""" or """"""""LPA,"""""""" is now known to function through a set of 3 cognate G-protein coupled receptors LPA1-3 and has influences on the cerebral cortex. Determining the receptor-mediated LPA signaling in the cerebral cortex is the focus of the current proposal. In this competitive renewal, we will test the hypothesis that receptor-mediated LPA signaling acts upon neural precursor cells (NPCs) and young postmitotic neurons to alter cell number, survival and fate in the developing cerebral cortex. These hypotheses will be tested by 3 aims: 1) Determine the role of LPA signaling on NPC cell cycle progression, 2) Determine the role of LPA signaling on NPC and neuronal cell death, and 3) Determine the role of LPA signaling on neuronal differentiation. Loss-of-function analyses utilizing targeted genetic nulls of each LPA receptor will be pursued. Gain-of-function analyses will utilize a new cell culture system in which intact embryonic cortex can be grown ex vivo while maintaining normal anatomical landmarks; receptor over activation by exogenous LPA exposure will be complemented by retroviral-mediated expression of LPA receptors in normal tissue. In addition, rescue experiments utilizing retroviruses on LPA-null tissue will be pursued. It is notable that the small size of these lipid molecules makes them attractive targets for drug design, and results from this proposal could serve as a foundation for new therapies based upon lysophospholipid-mimetic drugs.
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