The regulatory mechanisms that make mature sperm cells in the mouse

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In multicellular organisms that reproduce sexually, gametes are the sole type of cells that convey genetic information to the next generation. In mice, the germ cell lineage appears at the epiblast stage of embryogenesis, and is separated from the somatic lineage. The emerging germ cells are called primordial germ cells or PGCs, where methylation in the genomic DNA eventually becomes almost completely erased, transiently making their epigenome profoundly different from that of the somatic cells. Then, in sperm cell precursors called prospermatogonia in embryonic testes, de novo DNA methylation takes place genome-wide. These cells subsequently become spermatogonia with the stem cell activity to proliferate in response to external signals, which underlies the life-long production of spermatozoa. Spermatogonia are unipotent stem cells, and a fraction of them differentiate into spermatocytes, in which the transcriptomic program is switched to execute the special cell division process called meiosis. Meiosis in males produces haploid spermatids, which then differentiate into spermatozoa having specific morphology and highly condensed chromatin. All of these consecutive processes are orchestrated by a number of genes, and a failure in any of them results in infertility.

In this issue, we have four review articles written by leading young scientists in mammalian germ cell biology. Kenjiro Shirane describes how DNA methylation patterns are established in the male and female germlines, especially how K4 and K36 methylation of histone H3 guide de novo DNA methylation in prospermatogonia and oocytes. Yu Kitadate and Shosei Yoshida describe how the stem cell population of spermatogonia is regulated. We will see that internal and external inputs are involved in the appropriate balancing of the self-renewal and differentiation activities of spermatogonia. Meiosis occurs only in germ cells, implying a specific program of transcriptome dynamics during the process. Kei-ichiro Ishiguro and Ryuki Shimada describe how the meiotic transcription program is initiated, and how the initiation of the program leads to temporal changes in the transcriptome through a regulatory cascade. In this process, Meiosin, which was previously recognized just as a hypothetical protein, plays a key role. Finally, Yuki Okada describes nuclear and cytosolic events in haploid spermatids that contribute to the formation of spermatozoa with highly condensed chromatin.

Altogether, these review articles highlight the sophisticated program of spermatogenesis that produces gametes having genomic, epigenomic and cellular integrity. Future research should uncover the whole picture of the cellular program of germ cell development, which is fundamentally encoded in the genome, and thus contribute to both basic biology and clinical applications.