Mina L Kojima, David C. Page, Alexander K. Godfrey, Dirk G. de Rooij, Maria M. Mikedis, Y. Q. Shirleen Soh, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Soh, Ying Qi Shirleen, Mikedis, Maria M., Kojima, Mina, Godfrey, Alexander Kamitsuka, Page, David C, and de Rooij, Dirk G.
The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase of mitosis. Here we show that, in mice, maintenance of an extended meiotic prophase I requires the gene Meioc, a germ-cell specific factor conserved in most metazoans. In mice, Meioc is expressed in male and female germ cells upon initiation of and throughout meiotic prophase I. Mouse germ cells lacking Meioc initiate meiosis: they undergo pre-meiotic DNA replication, they express proteins involved in synapsis and recombination, and a subset of cells progress as far as the zygotene stage of prophase I. However, cells in early meiotic prophase—as early as the preleptotene stage—proceed to condense their chromosomes and assemble a spindle, as if having progressed to metaphase. Meioc-deficient spermatocytes that have initiated synapsis mis-express CYCLIN A2, which is normally expressed in mitotic spermatogonia, suggesting a failure to properly transition to a meiotic cell cycle program. MEIOC interacts with YTHDC2, and the two proteins pull-down an overlapping set of mitosis-associated transcripts. We conclude that when the meiotic chromosomal program is initiated, Meioc is simultaneously induced so as to extend meiotic prophase. Specifically, MEIOC, together with YTHDC2, promotes a meiotic (as opposed to mitotic) cell cycle program via post-transcriptional control of their target transcripts., Author summary Meiosis is the specialized cell division that halves the genetic content of germ cells to produce haploid gametes. This reductive division is preceded by a preparative phase of the cell cycle, meiotic prophase I, during which several meiosis-specific chromosomal events occur. Across sexually reproducing organisms, prophase of meiosis I is dramatically longer than mitotic prophase. However, it was not known in mammals how and why meiotic prophase I is extended. We have identified a mouse mutant in which this extended prophase I is disrupted: germ cells lacking Meioc initiate meiosis, but prematurely proceed to metaphase. Mutant male meiotic germ cells mis-express a cell cycle regulator that is normally expressed in mitotic male germ cells, suggesting that Meioc is required for germ cells to properly transition to a meiotic cell cycle program. Biochemical analyses of proteins and transcripts that associate with MEIOC protein suggest that MEIOC may promote the transition from a mitotic to meiotic cell cycle program by post-transcriptionally regulating target transcripts. Our studies indicate that in mammals, as in other sexually reproducing organisms, meiotic prophase I must be extended to allow time for meiotic chromosomal events to reach completion.