# POU4F2/Brn-3b is Essential for Spermatogenesis and its Disruption is Linked to Male Infertility in Mice and Humans

## TL;DR

This study shows that the Brn-3b protein is crucial for sperm production and male fertility in both mice and humans.

## Contribution

The study identifies Brn-3b as a key regulator of spermatogenesis and links its disruption to male infertility.

## Key findings

- Brn-3b knockout mice show reduced sperm counts, impaired motility, and structural defects in sperm.
- RNA-seq reveals Brn-3b regulates genes critical for sperm development and mitochondrial function.
- Human infertile men show reduced Brn-3b levels and potentially harmful genetic variants.

## Abstract

Male infertility is rising globally, yet its causes remain unclear. This study identifies the transcription factor Brn-3b (POU4F2) as essential for spermatogenesis and sperm function. Brn-3b is highly expressed in mature spermatids and infertility in constitutive male Brn-3b knockout (KO) mice is characterised by structural and functional testicular changes such as reduced sperm counts, impaired motility and ultrastructural defects including disrupted acrosomes and defects in the mitochondria and flagella. RNA-seq analyses reveal significant changes in Brn-3b-dependent regulation of genes essential for sperm development, mitochondrial function, and microtubule-based movement. This was confirmed using qRT-PCR with reduced expression of associated genes e.g. Spata13, Dnah6, Cox7a1 and upregulation of genes linked to inflammation and ECM remodelling (e.g., Ptges, MMP2). Human studies showing reduced Brn-3b in infertile men, e.g. with Klinefelter syndrome validated these findings. Exome sequencing identifying potentially deleterious variants in infertile men, suggest Brn-3b as a promising target for understanding and diagnosing male infertility.