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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001723-05
Application #
6919978
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (02))
Program Officer
Sieber, Beth-Anne
Project Start
1999-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2005
Total Cost
$121,500
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel et al. (2015) Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex. Brain Struct Funct 220:3701-20
Castilla-Ortega, Estela; Rosell-Valle, Cristina; Blanco, Eduardo et al. (2013) Reduced wheel running and blunted effects of voluntary exercise in LPA1-null mice: the importance of assessing the amount of running in transgenic mice studies. Neurosci Res 77:170-9
Peterson, Suzanne E; Westra, Jurjen W; Rehen, Stevens K et al. (2011) Normal human pluripotent stem cell lines exhibit pervasive mosaic aneuploidy. PLoS One 6:e23018
Castilla-Ortega, Estela; Hoyo-Becerra, Carolina; Pedraza, Carmen et al. (2011) Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA? receptor knockout mice. PLoS One 6:e25522
Castilla-Ortega, Estela; Sanchez-Lopez, Jorge; Hoyo-Becerra, Carolina et al. (2010) Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor. Neurobiol Learn Mem 94:73-82
Santin, L J; Bilbao, A; Pedraza, C et al. (2009) Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits. Genes Brain Behav 8:772-84
Rivera, R; Chun, J (2008) Biological effects of lysophospholipids. Rev Physiol Biochem Pharmacol 160:25-46
Peterson, Suzanne E; Westra, Jurjen W; Paczkowski, Christine M et al. (2008) Chromosomal mosaicism in neural stem cells. Methods Mol Biol 438:197-204
Tager, Andrew M; LaCamera, Peter; Shea, Barry S et al. (2008) The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14:45-54
Lee, Chang-Wook; Rivera, Richard; Dubin, Adrienne E et al. (2007) LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation. J Biol Chem 282:4310-7

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