Infertility effects 10% of the population with half of cases attributed to the malepartner, resulting in financial, emotional, and social burdens when trying to conceive. Male infertility may be attributed to disruptions in spermatogenesis, which prevents spermatogonia from becoming mature spermatozoa necessary for fertilization. However, the mechanisms behind male infertility and contributing genetic factors are not fully elucidated. One such factor is Ring finger protein 216 (RNF216/TRIAD3), an E3 ubiquitin ligase in the RING-between-RING (RBR) subfamily with mutations identified in patients with Gordon Holmes Syndrome (GHS), a neurodegenerative disorder with male reproductive dysfunction. Additionally, global deletion of ubiquitous RNF216 in mice revealed essentiality of RNF216 in male fertility. However, the germ cell requirement and mechanism of RNF216 in male reproduction and GHS are unclear. To address this, I generated novel transgenic mouse lines to examine expression and localization of RNF216 in vivo, conditionally knockout RNF216 in male germ cells, and model the human GHS ubiquitin ligase inactivating RNF216 mutation. First, I characterized RNF216 expression in male germ cell populations that is seminiferous tubule stage-specific and localized within sub-nuclear domains. Furthermore, I discovered RNF216 is intrinsically required in male germ cells for spermatogenesis and fertility but is dispensable for spermatogonia function and survival. Finally, I determined the human GHS mutation led to progressive germ cell degeneration and infertility, demonstrating RNF216-directed ubiquitination is essential for spermatogenesis. These data definitively show RNF216 has a pivotal role in male germ cell biology, GHS reproductive etiology, and infertility.
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