INVESTIGATING RETINOIC ACID REGULATION IN THE POSTNATAL TESTIS

Elizabeth Balconi Evans

Spermatogenesis is the tightly regulated process in which spermatogonial stem cells differentiate to form mature spermatozoa. One possible way to regulate spermatogenesis is through manipulating the active metabolite of vitamin A, retinoic acid (RA). RA is necessary for the maturation of spermatogonia and the proper entry of germ cells into meiosis during spermatogenesis. Additionally, excess RA has been shown to cause germ cell death in both neonatal and adult animals. The hypothesis underlining this research is that RA is available within the testis in a pulsatile manner. Therefore, the degradation of RA must be tightly regulated in order for the pulse to occur. The cytochrome P450 enzymes, CYP26A1 and CYP26B1 are known to degrade RA within the embryonic gonad, however their role during spermatogenesis has not been fully elucidated. We recently reported a unique method for synchronizing spermatogenesis without affecting fertility by manipulating RA levels within the neonatal testis. Using this protocol, combined with the RiboTag transgenic mouse line, we have mapped the Sertoli and germ cell "translatome" during the initial synchronized wave of spermatogenesis. Using microarray analysis, we identified 392 and 194 germ or Sertoli cells transcripts, respectively, that dynamically change during spermatogonial differentiation, division and the onset of meiosis. These datasets represent the first transcriptional analysis of spermatogonial differentiation, division, and meiotic onset. The roles of CYP26A1 and CYP26B1 have been examined in the postnatal testis by creating dual knockouts of CYP26A1 and CYP26B1 in Sertoli or germ cells. Deletion of Cyp26a1 and Cyp26b1 in germ or Sertoli cells resulted in vacuolization within the seminiferous tubules and delayed spermatid release. Furthermore, germ and Sertoli cells knockout of both of these enzymes caused an increase in the number of differentiating spermatogonia. These data indicate that both Cyp26a1 and Cyp26b1 in either Sertoli or germ cells are important for the proper progression of spermatogenesis. Understanding the role CYP26 enzymes play in maintaining germ cell development may lead to developing new techniques for treating infertility and possibly identify targets for male contraception.

INVESTIGATING RETINOIC ACID REGULATION IN THE POSTNATAL TESTIS

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