# Loss of full-length DAZL isoform disrupts PABPC1-dependent translational regulation and meiosis

## TL;DR

This study shows that losing a specific version of the DAZL protein disrupts sperm and egg development, causing infertility in both males and females.

## Contribution

The study reveals a novel role of DAZL isoforms in meiotic regulation through PABPC1-dependent translational control.

## Key findings

- Loss of full-length DAZL causes male infertility due to spermatocyte apoptosis and arrested spermatid development.
- DAZL_FL is essential for female fertility, as its absence leads to primordial follicle apoptosis and failed follicle recruitment.
- DAZL_FL interacts with PABPC1 to regulate translation of meiotic genes, while DAZL_Sh cannot.

## Abstract

Alternative splicing (AS) events are exceptionally active during spermatogenesis, enhancing the diversity of the testicular transcriptome and proteome. In mouse testes, the germ cell-specific RNA-binding protein DAZL undergoes alternative splicing to produce two isoforms: a full-length DAZL (DAZL_FL) and a short isoform lacking exon 8 (DAZL_Sh). While DAZL is a hallmark of germ cell development, the physiological roles of its alternative splicing, and the distinct functions of these two isoforms remain yet to be fully elucidated. To investigate this, we disrupted alternative splicing of Dazl by generating DAZL short isoform only mice via deletion of the DAZL exon 8 and found that the resulting loss of DAZL_FL led to male infertility, characterized by extensive spermatocyte apoptosis and arrest of spermatid development. Ribosome profiling (Ribo-seq) revealed that loss of DAZL_FL downregulated the translation of meiotic genes specifically bound by DAZL. Mechanistically, DAZL_Sh failed to interact with Poly(A) Binding Protein Cytoplasmic 1 (PABPC1), resulting in impaired translation of DAZL-targeted germ cell transcripts. In females, DAZL_FL ablation caused complete infertility, marked by massive primordial follicle apoptosis and failure of primary follicle recruitment, highlighting a shared role for DAZL_FL in meiotic regulation in both sexes. Our findings established DAZL/PABPC1 complex formation as a pivotal mechanism controlling meiotic progression. By functionally dissecting DAZL isoforms, we uncovered a critical role of Dazl alternative splicing during spermatogenesis and folliculogenesis, further expanding the roles of DAZL in germ cell development and thereby providing novel genetic causes and potential therapeutic targets for azoospermia and primary ovarian insufficiency.