Hybrid male sterility in house mice: meiotic checkpoints, chromosomal asynapsis, and the Prdm9-Mir465...

Meiosis is a key stage in the sexual reproduction of eukaryotes. It ensures the continuity of genetic information from generation to generation, while also generating the necessary genetic diversity for the survival and evolution of species. Meiotic progression is often compromised in hybrids between related subspecies, resulting in hybrid sterility and irreversible reproductive isolation. However, most genetic studies to date have not focused on the meiotic phenotypes of hybrid sterility and their molecular mechanisms. This review examines the genetic architecture, as well as the meiotic and molecular phenotypes, of hybrid sterility in the house mouse (Mus musculus) and other mammals. House mice subspecies provide the most widely understood mammalian model of hybrid sterility because of their recent evolutionary divergence, powerful genetic tools and comprehensive cytology of individual meiotic stages. We emphasize the potential impact of meiotic surveillance mechanisms, checkpoint pathways, particularly those leading to the meiotic sex chromosome inactivation and we draw parallels between intraspecific genic and chromosomal sterility and intersubspecific hybrid sterility. Finally, we review the Prdm9-Mir465 incompatibility system, the only vertebrate hybrid sterility model for which the three major genetic components necessary and sufficient to recreate the hybrid sterility genome have been identified. This three-part genetic architecture links Prdm9-dependent meiotic recombination hotspot activation, heterosubspecific homolog pairing, and microRNA-mediated meiotic checkpoint regulation to spermatogenic arrest and male sterility. MiR-465 is apparently the first microRNA which functions as a guardian of the pachytene checkpoint.