INVESTIGATING THE ROLE OF RETINOIC ACID SIGNALING IN THE STEROIDOGENIC CELLS OF THE MOUSE TESTIS AND EPIDIDYMIS

Estela Jasmin Jauregui

INVESTIGATING THE ROLE OF RETINOIC ACID SIGNALING IN THE STEROIDOGENIC CELLS OF THE MOUSE TESTIS AND EPIDIDYMIS Abstract by Estela Jasmin Jauregui, Ph.D. Washington State University July 2017 Chair: Michael Griswold Clinical research is currently being performed to determine whether drugs that manipulate intratesticular testosterone and retinoid concentrations could be used to treat male infertility. Testosterone and retinoic acid (RA), the active metabolite of vitamin A, signaling pathways are critical for normal spermatogenesis and epididymal function. Although these two individual pathways have both been studied separately, crosstalk between RA and testosterone has not been investigated. An interaction between the classical RA signaling pathway and the production of testosterone by the steroidogenic cells could have major repercussions in the development of drugs for fertility treatments. Therefore, this dissertation focuses on investigating the role of classical RA signaling in the steroidogenic cells of the testis, the Leydig cells, and epididymis, the principal cells. To better understand the steroidogenic cell function, we mapped the Leydig cell “translatome” across the different stages of the spermatogenic cycle in vivo. In this study, we identified Leydig cell-enriched genes that might be involved in the regulation of cyclic germ cell development. Additionally, retinoic metabolism transcripts were identified in the Leydig cells, suggesting that classical RA signaling play a role in the steroidogenic cell function. Therefore, our subsequent studies focused on determining whether classical RA signaling is needed in the steroidogenic cells for their normal function. To investigate the role of classical RA signaling in the steroidogenic cells, we generated mice with steroidogenic cells unable to perform classical RA signaling by utilizing a dominant negative form of retinoic acid receptor alpha (RAR-DN). The expression of the RAR-DN in the Leydig cells caused spermatogenic errors consistent with pachytene spermatocytes apoptosis; a similar phenotype observed in mice either lacking or containing only low levels of testosterone. Surprisingly, the expression of the RAR-DN in the principal cells revealed that the epithelial lining of the caudal ducts had undergone squamous metaplasia and induced an inflammatory response. These data indicate that the classical RA signaling pathway is needed in the mouse steroidogenic cells for their normal function, and thus, for male fertility.

INVESTIGATING THE ROLE OF RETINOIC ACID SIGNALING IN THE STEROIDOGENIC CELLS OF THE MOUSE TESTIS AND EPIDIDYMIS

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