The production of gametes in mammals is an elaborate process that begins during embryogenesis and continues during the reproductive life of the organism. Gametogenesis involves the production of highly specialized cells with unique organelles designed to accomplish the union of sperm and egg at fertilization. The timely production of developmentally important products involves the regulated translation of mRNAs that have accumulated earlier during gametogenesis. Deviation from the wild-type timing of translation can cause cessation of gametogenesis and lead to sterility in mice. Loss of posttranscriptional control may be responsible for a significant percentage of idiopathic male infertility in humans. Our understanding of the genetic control and molecular mechanisms of posttranscriptional control during gametogenesis is woefully incomplete. The long-term goal of this proposal is to elucidate the mechanisms of translational control during spermatogenesis. The knowledge gained from these studies may be useful in the genetic assessment of male infertility in humans, and lead to the development of male contraceptives designed to disrupt essential regulatory steps during normal spermatogenesis. Our studies will focus on the regulation of the spermatid-specific protamine mRNAs. Transgenesis will be used to test specific models for the function of previously identified regulatory sequences in the protamine I, Prm1, 3' untranslated region. A screen will be performed to identify new genes that regulate the translational repression of Prm1 in round spermatids. Mutation of the Prbp gene results in defects in the translational activation of the protamine mRNAs in elongated spermatids and cause male sterility. DNA arrays will be screened to determine the specificity of the Prbp mutant phenotype. Several approaches will be used to pursue the role of PRBP in translational activation. Lastly, targeted mutagenesis will be used to investigate the function of murine Y box proteins in posttranscriptional control.
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