Novel Factors that Regulate GnRH Neuronal Development

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DESCRIPTION (provided by applicant): Gonadotropin releasing hormone (GnRH) neurons display a unique pattern of a developmentally programmed neuronal migration and gene expression. The mechanisms that control their precisely timed pattern of migration from the olfactory placode to the forebrain are unknown; however, disorders that cause a failure of neuronal migration ultimately result in a failure of sexual maturation. The difficulties inherent in the study of GnRH neurons due to their small number and heterogenous, dispersed population in vivo was advanced with the development of GnRH producing cell lines: GT1-7 derived from postmigratory GnRH neurons in the forebrain that make abundant GnRH, and Gn10/NLT cells derived from migratory GnRH neurons in the olfactory area that make little GnRH. Based on the divergent phenotype of the two GnRH producing cells, we used differential display polymerase chain reaction (DDPCR) to identify divergently expressed gene products. One of the cDNAs cloned was Adhesion related kinase, (Ark), a member of a novel family of receptor tyrosine kinases (Ark/Axl, Tyro3 and Mer), whose extracellular domain has features of a cell adhesion molecule. The Ark cDNA was expressed in the migratory Gn10/NLT cells and not in the postmigratory GT1-7 cells. Studies have confirmed the hypothesis that Ark and its ligand, growth arrest specific gene 6 (Gas6), may play a role in GnRH neuronal migration, protection from programmed cell death and repression of GnRH synthesis. This proposal will dissect further the role of Gas6/Ark and its family member, Tyro3, in GnRH neuronal migration and the mechanism by which Ark signaling inhibits GnRH transcription. GnRH neuronal cell systems will provide the foundation to then confirm in an in vivo head slice model and studies using single and double transgenic knockout models of Ark and Tyro3. Together this investigation will advance our understanding of the mechanisms that underly GnRH neuronal migration and gene expression across development. They will also provide new candidate genes that may underly human GnRH deficiency syndromes and identify novel targets for pro or antifertility agents. Studies will give insight into general mechanisms of neuronal migration that could impact on the treatment of neurodegenerative diseases.