The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells

Abstract

Absence of mitosis and meiosis are distinguishing properties of male germ cells during late fetal and early neonatal periods. Repressors of male germ cell meiosis have been identified, but mitotic repressors are largely unknown, and no protein repressing both meiosis and mitosis is known. We demonstrate here that the zinc-finger protein BNC2 is present in male but not in female germ cells. In testis, BNC2 exists as several spliced isoforms and presumably binds to DNA. Within the male germ cell lineage, BNC2 is restricted to prospermatogonia and undifferentiated spermatogonia. Fetal prospermatogonia that lack BNC2 multiply excessively on embryonic day (E)14.5 and reenter the cell cycle prematurely. Mutant prospermatogonia also engage in abnormal meiosis; on E17.5, Bnc2−/− prospermatogonia start synthesizing the synaptonemal protein SYCP3, and by the time of birth, many Bnc2 −/− prospermatogonia have accumulated large amounts of nonfilamentous SYCP3, thus appearing to be blocked at leptonema. Bnc2 −/− prospermatogonia do not undergo proper male differentiation, as they lack almost all the mRNA for the malespecific methylation protein DNMT3L and have increased levels of mRNAs that encode meiotic proteins, including STRA8. Bnc2 −/− prospermatogonia can produce spermatogonia, but these enter meiosis prematurely and undergo massive apoptotic death during meiotic prophase. This study identifies BNC2 as a major regulator of male germ stem cells, which is required for repression of meiosis and mitosis in prospermatogonia, and for meiosis progression during spermatogenesis. In view of the extreme evolutionary conservation of BNC2, the findings described here are likely to apply to many species.

MicroRNAs and DNA methylation as epigenetic regulators of mitosis, meiosis and spermiogenesis

“…Demethylation of testis-specific genes may be required for meiotic initiation, since DNA methyltransferases are attenuated significantly in type B spermatogonia and preleptotene spermatocytes. Recently it has been reported that down-regulation of DNMT3L may increase the expression of the premeioticspecific gene-STRA8, leading to the onset of meiosis prematurely (Vanhoutteghem et al 2014). In addition, it has been revealed that 5mC-specific dioxygenase (TET1) can mediate the demethylation of the locus-specific genes, including the meiotic genes, and promotes the meiotic initiation through the activation of these genes in oocytes (Yamaguchi et al 2012).…”

Gene knockout of Zmym3 in mice arrests spermatogenesis at meiotic metaphase with defects in spindle assembly checkpoint

“…Abnormal gene expression during spermatogonial differentiation leads to either a spermatogenic arrest at a pre-meiotic stage or a precocious entry of meiosis. 3, 4 …”

Morphogenetic chromatin reorganization aspects at the preleptoten stage of human spermatogenesis

“…Для модельных объектов предложены кандидатные гены, экспрессирующие консервативный белок подавления митоза в мужских ПК во время про-должительного периода блока их пролиферации до по-лового созревания. Сперматогонии мышей при недо-статке белка базонуклеин 2 (bnc2) рано вступают в мейоз [12]. Консервативный белок bnc2 присутству-ет только в мужских ПК, останавливает митоз и бло-кирует мейоз, связываясь с ДНК.…”

“…В настоящий момент информация о динамике пре-лептотенных преобразований в сперматогенезе фраг-ментарна [4,[11][12][13]. Эта стадия непосредственно следу-ет за последним синтезом ДНК перед началом мейоза.…”