Spermatogenesis begins in humans and mice with the segregation of spermatogonia into distinct undifferentiated and differentiating populations. Undifferentiated spermatogonia retain stem cell potential, while differentiated spermatogonia eventually become spermatozoa. This delicate balance must be maintained, as defects can result in testicular cancer or infertility. Currently, little is known about the gene products and signaling pathways directing these critical cell fate decisions. It was recently reported that precocious administration of retinoic acid (RA) induced differentiation of spermatogonia in the neonatal testis, and this was accompanied by enhanced translation of selected mRNAs in spermatogonia. This indicates a novel mechanism by which RA signaling, which is required for germ cell development, regulates the proteome of spermatogonia during development. The objective of this project is to identify the mechanisms by which RA regulates mRNA metabolism and utilization in spermatogonia. The central hypothesis is that RA directs spermatogonial differentiation by enhancing translation of preexisting repressed mRNAs through activation of mTOR. This central hypothesis will be tested by the following aims: 1 - determine how RA activates translation of repressed spermatogonial mRNAs and 2 - determine the requirement for kinase signaling in RA-mediated translational activation in vivo. Together, results from these aims will clarify mechanisms by which RA regulates gene expression during spermatogonial differentiation. This will provide a significant advance in our understanding of the molecular mechanisms underlying germ cell fate decisions at the initiation of spermatogenesis.
The consistent differentiation of spermatogonia in response to retinoic acid (RA) in the testis ensures fertility throughout the male reproductive lifespan. Particularly little is known about gene regulation as spermatogonia differentiate, or the manner in which disruption of the normal expression pattern can lead to abnormalities such as infertility or testicular cancer. The results from this project will significantly advance understanding of a novel mode of posttranscriptional gene regulation directed by RA.
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