DDX5 plays essential transcriptional and post-transcriptional roles in the maintenance and function of spermatogonia

Abstract

Mammalian spermatogenesis is sustained by mitotic germ cells with self-renewal potential known as undifferentiated spermatogonia. Maintenance of undifferentiated spermatogonia and spermatogenesis is dependent on tightly co-ordinated transcriptional and post-transcriptional mechanisms. The RNA helicase DDX5 is expressed by spermatogonia but roles in spermatogenesis are unexplored. 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. We demonstrate that DDX5 regulates appropriate splicing of key genes necessary for spermatogenesis. Moreover, DDX5 regulates expression of cell cycle genes in undifferentiated spermatogonia post-transcriptionally and is required for cell proliferation and survival. 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. Combined, our data reveal a critical multifunctional role for DDX5 in regulating gene expression programmes and activity of undifferentiated spermatogonia.

Critical roles of the ddx5 gene in zebrafish sex differentiation and oocyte maturation

“…2, 5; Table 1). This phenotype was quite different from the failure of Ddx5-disrupted male mice on spermatogenesis 14 . The expression of ddx5 was widespread in whole embryos and was not specifically detected in the primordial germ cells at 24 hpf (Fig.…”

“…* email: akawahara@yamanashi.ac.jp www.nature.com/scientificreports/ developed as fertile males, while a small population of ddx5-deficient mutants developed as infertile females with small ovaries. Such phenotypes are different from those of vasa/ddx4-disrupted zebrafish and Ddx5-disrupted male mice 12,14 . We found that apoptotic cell death was increased in thick immature gonads (presumptive developing ovaries) of ddx5-deficient mutants at 31 dpf.…”

“…The human DDX5 gene is expressed in spermatogonia 13 . The ablation of the Ddx5 gene using tamoxifen-inducible Ddx5 knockout male mice results in the rapid loss of spermatogonia 14 . Thus, the physiological function of ddx5 in other vertebrates is not known.…”

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

“…H1T2-chromatin IP/MS analysis also identi ed YbX2, another potential mRNA repressor involved in the regulation of translation whose knockout resulted in male infertility and azoospermia condition (79). Notably we also found Ddx5 in our list of H1T2chromatin interacting proteins, which is considered to be an essential protein for both transcriptional and posttranscriptional roles in the maintenance and function of spermatogonia (80). PABP1 was the other important protein pulled down with H1T2-chromatin, whose function has been extensively characterized in germ cells and shown to have important roles in mRNA stability and translation (81).…”

Genome-wide occupancy reveals the localization of H1T2 (H1fnt) to repeat regions and a subset of transcriptionally active chromatin domains in rat spermatids

“…H1T2-chromatin IP/MS analysis also identi ed YbX2, another potential mRNA repressor involved in the regulation of translation whose knockout resulted in male infertility and azoospermia condition (82). Notably we also found Ddx5 in our list of H1T2chromatin interacting proteins, which is considered to be an essential protein for both transcriptional and posttranscriptional roles in the maintenance and function of spermatogonia (83). PABP1 was the other important protein pulled down with H1T2-chromatin, whose function has been extensively characterized in germ cells and shown to have important roles in mRNA stability and translation (84).…”