Identification of germ cell-specific Mga variant mRNA that promotes meiotic entry via impediment of a non-canonical PRC1

Abstract

Transition from mitosis to meiosis in cell division is a fundamental process of gametogenesis. This transition is thought to be largely controlled by the exchange of relative dominance between positive and negative regulation by the retinoic acid/Stra8 signal cascade and a non-canonical PRC1 (PRC1.6), respectively. We have previously demonstrated that germ cells have transcriptionally and/or post-translationally reduced levels of MAX, a component of PRC1.6, immediately prior to meiotic onset, leading to alleviation of the negative effect of PRC1.6 against meiotic onset. Here, we found that germ cells produced Mga variant mRNA bearing a premature termination codon (PTC) during meiosis as an additional mechanism to impede the function of PRC1.6. Our data indicated that spermatocytes and/or round spermatids produced an anomalous MGA protein lacking the bHLHZ domain from the variant mRNA and therefore functioned as a dominant negative regulator of PRC1.6 by exquisitely using their inefficient background of PTC-mediated nonsense-mediated mRNA decay. Thus, our data indicate that meiotic onset of male germ cells is controlled in a multi-layered manner in which both MAX and MGA, which constitute the core of PRC1.6 by their interaction, are at least used as targets to deteriorate the integrity of the complex to ensure initiation of meiosis. Significance StatementPRC1.6, a non-canonical PRC1, functions as a strong blocker of meiotic onset. Therefore, germ cells need to alleviate the function of the complex as a prerequisite for meiotic onset. The MGA/MAX heterodimer not only constitutes a core of PRC1.6, but also confers direct DNA-binding activity to the complex. We have previously demonstrated that germ cells reduce Max amounts prior to meiotic onset to inactivate PRC1.6. In this study, we explored the possibility of an additional molecular mechanism that promotes meiotic onset via impediment of PRC1.6 functions as a safeguard system. Here, we demonstrate that meiotic germ cells specifically generate variant Mga mRNA by alternative splicing, which leads to production of a dominant negative regulator of PRC1.6.