INVESTIGATING MECHANISMS REGULATING MAMMALIAN SPERMATOGONIAL DIFFERENTIATION AND MEIOTIC INITIATION

Abstract

Spermatogonia differentiation and meiotic initiation are complex processes essential for male fertility. Despite knowing for nearly 60 years that retinoic acid (RA) is instrumental for successful production of functional sperm, molecular mediators that regulate spermatogonial differentiation and prepare male germ cells for meiosis are poorly defined. The work presented here is organized into chapters and demonstrates my efforts to develop new tools to study germ cell development and to employ these tools to investigate the role and the developmental timeframes of RA activity during differentiation and meiotic initiation. In chapter 1, I examine published studies on development of germ cells starting at establishment of male germline in fetus to production of functional sperm in adult and highlight significant gaps in knowledge that are addressed with my work. In chapter 2, I describe negative effects of Everolimus, a pharmaceutical compound commonly used to treat cancer, on male fertility in mice. In chapter 3, I identify a new fluorescent reporter mouse model used to isolate large, highly enriched, precise population of germ cell at specific stages of their development and present a new culture system to study male germ cells in vitro. In chapter 4, I test the requirement for RA signaling during spermatogenesis.