DAZL Regulates Germ Cell Survival through a Network of PolyA-Proximal mRNA Interactions

The RNA binding protein DAZL is essential for gametogenesis, but its direct in vivo functions, RNA targets, and the molecular basis for germ cell loss in Dazl-null mice are unknown.

Our results reveal a mechanism for DAZL-RNA binding and illustrate that DAZL functions as a master regulator of a post-transcriptional mRNA program essential for germ cell survival.

RNA binding proteins (RBPs) are potent post-transcriptional regulators of gene expression.

The necessity of the DAZ family of RBPs for germ cell survival is well established in multiple species. However, the direct targets, regulatory roles, and biological functions of these RBPs remained unclear. Our integrative analyses combining transgenic mice, FACS, and a panel of unbiased, transcriptome-wide profiling tools provide important insights into the molecular and biological functions of this important family of RBPs.

In conclusion, our study provides insights into the molecular basis of germ cell loss in Dazl KO mice and demonstrates that germ cell survival depends on a DAZL-dependent mRNA regulatory program. Given the functional conservation between mouse DAZL, human DAZL, and DAZ (), our findings shed light on the molecular basis for azoospermia in 10%–15% of infertile men with Y chromosome microdeletions. The RNA targets of DAZL extend far beyond germ cell-specific genes and include many that encode core components of macromolecular complexes present in all proliferating cells. Therefore, our findings may also be relevant to other human diseases because Dazl is a susceptibility gene for human testicular cancer () and is amplified or mutated in nearly 30% of breast cancer patient xenografts examined in a single study (). We propose a general model (Figure S7) whereby DAZL binds a vast set of mRNAs via polyA-proximal interactions facilitated by PABPC1-polyA binding and post-transcriptionally enhances the expression of a subset of mRNAs, namely a network of genes that are essential for cell-cycle regulation and mammalian germ cell maintenance. These observations provide insights into molecular mechanisms by which a single RBP is recruited to its RNA targets and coordinately controls a network of mRNAs to ensure germ cell survival.