Abstract
Fertility across metazoa requires the germline-specific DAZ family of RNA-binding proteins. Here we examine whether DAZL directly regulates progenitor spermatogonia using a conditional genetic mouse model and in vivo biochemical approaches combined with chemical synchronization of spermatogenesis. We find that the absence of Dazl impairs both expansion and differentiation of the spermatogonial progenitor population. In undifferentiated spermatogonia, DAZL binds the 3' UTRs of ~2,500 protein-coding genes. Some targets are known regulators of spermatogonial proliferation and differentiation while others are broadly expressed, dosage-sensitive factors that control transcription and RNA metabolism. DAZL binds 3' UTR sites conserved across vertebrates at a UGUU(U/A) motif. By assessing ribosome occupancy in undifferentiated spermatogonia, we find that DAZL increases translation of its targets. In total, DAZL orchestrates a broad translational program that amplifies protein levels of key spermatogonial and gene regulatory factors to promote the expansion and differentiation of progenitor spermatogonia.
Highlights
The germline-specific DAZ family of RNA-binding proteins functions in germ cell development across metazoa
We demonstrate that Dazl promotes expansion and differentiation of spermatogonial progenitors, independent of its embryonic requirement for germ cell 5 determination (Figure 6)
Via biochemical analyses in undifferentiated spermatogonia in vivo, we further demonstrate that DAZL accomplishes these functions by enhancing translation of thousands of genes, including recognized spermatogonial factors that promote proliferation or differentiation of undifferentiated spermatogonia
Summary
The germline-specific DAZ family of RNA-binding proteins functions in germ cell development across metazoa. This family is comprised of Y-linked DAZ and its autosomal homologs DAZL (DAZ-like) and BOULE, all of which contain a highly conserved RNA. Deletions encompassing the Y chromosome’s Azoospermia Factor C (AZFc) region, which contains all four copies of the DAZ gene, are the most common known genetic cause of 10 spermatogenic failure, accounting for 10% of cases of azoospermia (no sperm detected in semen) or severe oligozoospermia (abnormally low number of sperm detected in semen) in the absence of any physical obstruction (Girardi et al, 1997; Nakahori et al, 1996; Reijo et al, 1995; Simoni et al, 1997; Vogt et al, 1996). Dazl is expressed in the embryonic germ line as well as during adult oogenesis and spermatogenesis (Seligman and Page, 1998) and likely functions at multiple stages of germline development.
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