Neurogenin 3 is a critical downstream effector for STAT3-regulated differentiation of male germline stem cells
Kaucher, Amy V.
Oatley, Jon M.
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Sperm are vehicles for male genetic contribution to the next generation, and their formation relies on a series of germ cell differentiation events. Germ cell differentiation initiates with development of progenitors from a germline stem cell pool and further differentiation of these cells set the foundation for sperm production. Currently, the understanding of molecular pathways regulating differentiation is poorly understood within stem and progenitor germ cells. The molecule Signal Transducer and Activator of Transcription 3 (STAT3) regulates differentiation of progenitor spermatogonia but down-steam effectors are unknown. Also, expression of a second transcription factor Neurogenin 3 (NGN3) coincides with formation of progenitor germ cells but a functional role in differentiation has not been described. In this study, we hypothesized that expression of NGN3 is regulated by STAT3 in stem and progenitor germ cells to control differentiation. We found that expression of NGN3 colocalized with the activated form of STAT3 and NGN3 gene expression. Furthermore, STAT3 was found to bind the distal NGN3 promoter region in progenitor spermatogonia and regulate transcription. Moreover, inhibition of NGN3 expression in germline stem cells blocked the development of progenitors leading to germ cell differentiation arrest. Collectively, these results establish a critical mechanism for sperm production in mammals via activation of STAT3 regulating the expression of NGN3 to subsequently drive differentiation of stem and progenitor germ cells.