ART-27 Regulates Mammalian Spermatogonial Stem Cell Survival and Differentiation

• Main Author: Schafler, Eric D
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2016
• Subjects: Developmental biology; Genetics; Pharmacology
• ISBN: 1369332750; 9781369332759

Male mammals must simultaneously produce prodigious numbers of sperm and maintain an adequate reserve of stem cells to ensure continuous production of gametes throughout life. Failures in the mechanisms responsible for balancing germ cell differentiation and spermatogonial stem cell (SSC) self-renewal can result in infertility. We discovered a novel requirement for Androgen Receptor Trapped clone-27 (ART-27) in spermatogenesis by developing the first knockout mouse model for this gene. Constitutive deletion of ART-27 is embryonic lethal between e5.5 and 7.5 due to defects in extra-embryonic tissues. Conditional knockout in the male germline results in a rapid decline in pre-meiotic germ cell number that starts around day 6-7 post-partum, eventually leading to a Sertoli cell-only phenotype that does not recover in the adult. Gene expression analysis revealed that ART-27 deletion downregulates the transcription of genes governing SSC self-renewal, differentiation, and meiosis. These data are consistent with spermatogenic arrest before meiotic entry and the total lack of germ cells after day 23. Sertoli cell-specific knockout of ART-27 also results in germ cell loss, and we hypothesize this is due to disruption of androgen receptor signaling. Our study has revealed the first in vivo function for ART-27 in the mammalian germline as a regulator of distinct transcriptional programs in SSCs and differentiating spermatogonia.