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  • br Introduction Meiosis is the key step of gametogenesis

    2018-10-20


    Introduction Meiosis CGP-41251 is the key step of gametogenesis, which ensures the production of haploid gametes from their diploid precursors and the recombination of genetic materials from the parents. For lower eukaryotes such as yeasts, meiosis is initiated under unfavorable environmental conditions whereby the extracellular signals are integrated at the transcriptional level of master regulatory genes, which in turn activate the expression of downstream targets (van Werven and Amon, 2011). In mammals, meiosis initiation is believed to be mainly regulated by the production, storage, and metabolism of retinol and its metabolite retinoic CGP-41251 (RA) (Griswold et al., 2012). RA signaling is mediated by its target genes such as Stra8, which is essential for the initiation and progression of meiosis (Anderson et al., 2008; Baltus et al., 2006; Bowles et al., 2006; Koubova et al., 2006; Mark et al., 2008). Intrinsic factors such as DAZL (deleted in azoospermia-like) prepare diploid germ cells ready for meiosis initiation when extracellular signals are received (Lin et al., 2008). Somatic cells play important roles in mammalian meiosis initiation, partially because these cells govern the production and degradation of RA. Female germ cells initiate meiosis shortly after sex determination, while their male counterparts enter a quiescent state because their surrounding somatic cells, the Sertoli cells, express RA-metabolizing enzymes, such as CYP26b1, which effectively degrades RA before it can act upon the germ cells (Bowles et al., 2006; Koubova et al., 2006; MacLean et al., 2007). Paracrine factors such as FGF9 and intrinsic ones such as NANOS2 are also essential for meiosis inhibition and sex-specific gene expression in males (Bowles et al., 2010; Saba et al., 2013). After birth, a subpopulation of male germ cells turn into spermatogonial stem cells (SSCs), which undergo life-long self-renewal and differentiation to produce sperm. The attempts to generate gametes in vitro can be dated back to almost a century ago. During the early phase of this long journey, the strategy of organ/tissue culture of the gonads was used and several studies reported the derivation of spermatocytes using rodent testes or human testicular biopsy (Song and Wilkinson, 2012). This strategy reached maturity when the Ogawa group reported that pup testis explants supported the derivation of functional spermatids and sperm from either autologous spermatogonia or transplanted mouse SSCs (mSSCs) (Sato et al., 2011a, 2011b). However, this ex vivo model is not ideal for elucidating the mechanisms of meiosis due to the complex constituents of the culture system. Another direction of the effort was to use dissociated testicular cells to derive gametes. Although several studies reported that pachytene spermatocytes or even haploid spermatogenic cells can be derived in the germ cell/Sertoli cell co-cultures, the low efficiency also limits its value for research and practical applications (Sa et al., 2008; Tres and Kierszenbaum, 1983). Moreover, none of these studies used long-term SSC cultures, which make large-scale amplification and gene modification of germ cells possible. The third strategy for gamete generation is to induce gametes directly from pluripotent stem cells. About a decade ago, two groups showed that mouse embryonic stem cells (ESCs) could be induced to become oocytes or spermatids, respectively (Geijsen et al., 2004; Hubner et al., 2003). Several similar studies using human ESCs and induced pluripotent stem cells followed in subsequent years without functional evaluation of the induced gametes (Kee et al., 2009; Panula et al., 2010). One common problem of these studies is that the efficiency of gamete induction is unsatisfyingly low, except for one report that claimed that as much as 11% of the remaining cells after a long inducing period were haploids (West et al., 2010). Most of the other attempts to derive gametes in vitro succeeded in harvesting primordial germ cells (PGCs) but failed to generate haploid germ cells, and in many cases successful gametogenesis initiated by these induced PGCs was possible only after they were transplanted to the otherwise sterile gonads (Clark et al., 2004; Hayashi et al., 2011, 2012; Hayashi and Surani, 2009; Irie et al., 2014; Sugawa et al., 2015; Toyooka et al., 2003).