Potential function of KRAB zinc-finger proteins in murine spermatogenesis.

 

 

Kai Otsuka

(Assistant Professor,

at Tokyo University of Science, Faculty of Science and Technology)

 

More than half of the mammalian genome consists of transposable elements (TEs) which originated from retroviral invasions into ancestral genomes during evolution. TEs pose a potential risk for the host genome, as their transposition can disrupt endogenous genes and regulatory elements. To counteract this threat, host cells -especially germ cells, only the cell type that transmits its genome to the next generation- have developed a multi-layer defensive system against retroviruses, including piRNAs, DNA methylation, and other epigenetic machinery, to safeguard genome integrity.

Recently, we discovered that KRAB zinc-finger proteins (KZFPs), the most rapidly evolving transcription factors, bind to young TEs and serve repressive epigenetic marks, H3K9me3, in spermatogonia, suggesting an additional layer of genome protection against TEs. We also found an evolutionary relationship between KZFPs and their target TEs, implying that a co-opting arms race takes place in germlines in mammalian evolution. To elucidate the biological roles of KZFPs in male germline development, we newly generated mutant mice, which carry multiple KZFPs-cluster-deletions.

Our morphological analyses revealed a significant reduction of germ cells in the neonatal mutant testis at postnatal day (PD) 3. Notably, while nearly half of the tubules lacked germ cells, the remaining half retained normal germ cells, resulting in two distinct tubule populations. Interestingly, spermatogenesis appeared to progress normally, although was only observed in approximately half of the tubules as well. Additionally, a small but certain number of sperm were observed in the adult mutant cauda epididymis.

These observations led us to hypothesize that the role of KZFPs may not be involved in stem-cell maintenance, the progression of meiosis, or post-meiotic events but rather play a role in an earlier stage, such as embryonic germ cells. Here, we present the recent data in the mutant mice and discuss the biological significance of KZFPs in male germ cell development.