In the new grant period we will utilize the information we have extracted from our large microarray databases to focus on the process of spermatogonial maturation and the role of retinoids in that process. Our array data clearly identifies a retinoid responsive gene, termed Stra8, that is expressed in germ cells of the postnatal male and embryonic female as a precursor to entry into meiosis. Previous work in our laboratory and other laboratories has shown that a vitamin A deficiency blocks the conversion of undifferentiated spermatogonia to differentiating A1 spermatogonia. This observation suggests retinoic acid is required for the undifferentiated spermatogonia to enter into a differentiation pathway and ultimately into meiosis. Induction of the gene, Stra8, is a requirement and a reliable marker for this process. The action of retinoic acid and the subsequent changes in gene expression that occur, dramatically impact the maturation of spermatogonia and the onset of meiosis. Major parts of the proposed project are to more clearly define the response of spermatogonia to retinoic acid, to examine the response of the Stra8 gene in detail and to find other genes involved in the maturation process. In particular, we will focus on the potential role of 3 additional genes, Tex13, Xlr4 and an EST no. 1700013H16Rik which all share a pattern of expression that mirrors that of Stra8.
Three specific aims are proposed: 1. Define the retinoic acid response of the testis with regard to the somatic cells and the maturation of spermatogonia. 2. Define the transcriptional elements that regulate Stra8 expression and spermatogonial maturation. 3. Determine the cellular localization and direct interacting partners of Stra8, Tex13, Xlr4 and 1700013H16Rik in spermatocytes. This research project could potentially determine the molecular mechanisms that initiate spermatogenesis in the male germline. Knowledge about the actions of retinoic acid and the genes responsible for the entry of spermatogonia into the differentiation pathway could lead to new approaches to contraception.
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