The mammalian testis is an example of such a tissue where tightly co-ordinated transcriptional and post-transcriptional mechanisms harmonise to ensure lifelong maintenance of fertility through the continual production of mature spermatozoa 1. The balance between stem cell self-renewal and differentiation can be regulated through extrinsic stimuli, including growth factors produced in a supportive niche, as well as cell intrinsic factors such as transcription factors and post-transcriptional gene regulatory mechanisms. The maintenance of adult tissue integrity and function is often dependent upon a population of resident stem cells that self-renews and generates differentiating cells. Combined, our data reveal a critical multifunctional role for DDX5 in regulating gene expression programmes and activity of undifferentiated spermatogonia. DDX5 can also act as a transcriptional co-activator and we demonstrate that DDX5 interacts with PLZF, a transcription factor required for germline maintenance, to co-regulate select target genes. Moreover, DDX5 regulates expression of cell cycle genes in undifferentiated spermatogonia post-transcriptionally and is required for cell proliferation and survival. We demonstrate that DDX5 regulates appropriate splicing of key genes necessary for spermatogenesis. Using an inducible knockout mouse model, we characterise an essential role for DDX5 in spermatogonial maintenance and show that Ddx5 is indispensable for male fertility. The RNA helicase DDX5 is expressed by spermatogonia but roles in spermatogenesis are unexplored. Maintenance of undifferentiated spermatogonia and spermatogenesis is dependent on tightly co-ordinated transcriptional and post-transcriptional mechanisms. Mammalian spermatogenesis is sustained by mitotic germ cells with self-renewal potential known as undifferentiated spermatogonia.
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