Translational control during fetal male germ cell development

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DESCRIPTION (provided by applicant): Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. The control of mRNA translation is essential for fetal male germ cel (gonocyte) development. Specific RNA binding proteins are required to block meiotic initiation and maintain gonocytes in a quiescent state prior to their transition to spermatogonia after birth. Little is known about the proteins or mechanisms that mediate translational control during this period. The lack of known target mRNAs for such binding proteins has impeded the investigation of translational control mechanisms. We have recently identified such a target in the reproductive homeobox gene, Rhox13, which is transcribed but not translated in gonocytes of the fetal mouse testis. RHOX13 protein expression is repressed by NANOS2 in the fetal testis and stimulated by retinoic acid (RA) in the neonatal testis. We will utilize Rhox13 and the fetal to neonatal male germ cel transition as a model system to determine the mechanisms by which mRNAs in the fetal testis are repressed but then move to a translating state in response to RA in the neonatal testis. Our results will significantly advance understanding of translational repression and RA-modulated gene regulation during male germ cell development. Results from this work will guide our design of a genome-wide translational state array analysis to reconcile global differences between the transcriptome and proteome of the fetal and neonatal testis. PUBLIC HEALTH RELEVANCE: Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. !