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  • br Expression of DNMTs during testicular development


    Expression of DNMTs during testicular development In most multicellular organisms, male and female germ cells are the origin of development of an organism, and they provide inheritance of genetic and epigenetic information across the generations. Primordial germ cells (PGCs) derive from a subset of cells in the epiblast layer at embryonic day (E)6.5–E7.5 in mouse (Matsui and Mochizuki, 2014) (). Then, they begin to migrate from the epiblast to the hindgut at E7.5–E9 and reach the genital ridge at E9.5–E11.5 in mouse (Saitou and Yamaji, 2012) (). The PGCs colonize in the primitive gonad under the control of c-kit and its ligand interaction. Importantly, they undergo many mitotic divisions during migration and colonization (Richardson and Lehmann, 2010). In humans, the primitive gonad at an undifferentiated state until 7 weeks of embryonic improvement develops into male gonad hereafter, and while the medullar region transforms into testis, the cortical area gradually regresses. Notably, the sex determining region Y (SRY) gene located on the short arm of the Y chromosome regulates the testes determining factor (TDF) providing testicular development (Harley and Goodfellow, 1994). Spermatogenesis is a complex process started at the early stage of fetal development, and includes three main stages: mitosis, meiosis and spermiogenesis (). The gonocytes differentiate from PGC at E13.5 in mice. As already known, the gonocytes (fetal and neonatal germ cells) enter the primordial testis, in which they reach the MK-2048 membrane of developing seminiferous tubules and then differentiate into type A spermatogonia at day six postpartum. There are two types of type A spermatogonia: type A dark spermatogonia (Ad), type A pale spermatogonia (Ap). The type Ad cells possess dark nuclei and replicate indefinitely to supply spermatogonia for spermatogenesis. The type Ap cells with pale nuclei undergo mitotic division to produce type B spermatogonia. In the spermatogonial stage, type B spermatogonia derived from a subset of type A pale spermatogonia could be identified on day eight postpartum (Bellve et al., 1977). The type B spermatogonia are the progenitor cells that undergo many mitotic divisions and gradually migrate towards the seminiferous lumen. Then, type B spermatogonia differentiate into primary spermatocytes once the organism reaches sexual maturity. The primary spermatocytes undergo one round of meiosis to form secondary spermatocytes, which undergo the second round of meiosis to form round spermatids in the meiotic stage. In the spermiogenesis stage, the round spermatids undergo important structural and nuclear changes to create mature spermatozoa (Chocu et al, 2012, Wang, Xu, 2015). In PGC, DNA methylation marks in the parental genome are gradually erased as a result of global DNA demethylation (Popp et al., 2010), and these marks are re-established during early male germ cell development (Davis et al, 1999, Lees-Murdock et al, 2003). The re-establishment of DNA methylation is largely carried out by the specific DNA methyltransferases, DNMT3A, DNMT3B and DNMT3L (Kato et al., 2007). It is important to note that global DNA demethylation also happens during early embryonic development independent from that which occurs in the PGC (Mayer et al, 2000, Oswald et al, 2000). Additionally, it has been shown that male and female pronuclei exhibit distinct demethylation patterns after fertilization (Santos et al., 2005). Note that the dynamic expression of the DNMT in oocytes at different development stages and in the early embryos is comprehensively discussed in a recently published review article (Uysal et al., 2015). The re-establishment of DNA methylation in the male germ cells is carried out in prospermatogonia or gonocytes (Saitou et al., 2012). Interestingly, a high rate of DNA methylation is attained in the mitotically arrested gonocytes during prenatal development. The major methylation mechanisms, de novo and maintenance methylation work to create new methylation marks on DNA and to maintain previously established methylation marks in mitotically active spermatogonia and primary spermatocytes at prophase I, respectively, whereas maintenance methylation occurs only in male germ cells undergoing mitotic divisions (Oakes et al., 2007). It is important to note that general DNA methylation levels in the male germ cells are at lower profiles than in the somatic cells (Urdinguio et al., 2015). In a detailed work, Abe et al. (2011) revealed that DNA methylation profiles are at lower levels in the male germ cells than those of somatic cells between E11.5 and 15.5 of early development. However, the methylation status of male germ cells increases at E17.5, in which methylation marks begin to MK-2048 be largely established in mice (Abe et al., 2011).