Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling

Abstract

Meiosis is a unique type of cell division that is performed only by germ cells to form haploid gametes. The switch from mitosis to meiosis exhibits a distinct sex-specific difference in timing, with female germ cells entering meiosis during fetal development and male germ cells at puberty when spermatogenesis is initiated. During early fetal development, bipotential primordial germ cells migrate to the forming gonad where they remain sexually indifferent until the sex-specific differentiation of germ cells is initiated by cues from the somatic cells. This irreversible step in gonadal sex differentiation involves the initiation of meiosis in fetal ovaries and prevention of meiosis in the germ cells of fetal testes. During the last decade, major advances in the understanding of meiosis regulation have been accomplished, with the discovery of retinoic acid as an inducer of meiosis being the most prominent finding. Knowledge about the molecular mechanisms regulating meiosis signaling has mainly been established by studies in rodents, while this has not yet been extensively investigated in humans. In this review, the current knowledge about the regulation of meiosis signaling is summarized and placed in the context of fetal gonad development and germ cell differentiation, with emphasis on results obtained in humans. Furthermore, the consequences of dysregulated meiosis signaling in humans are briefly discussed in the context of selected pathologies, including testicular germ cell cancer and some forms of male infertility.

Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development

“…In the ovary germ cells enter meiosis in fetal life, whereas in fetal testes the meiotic entry is actively inhibited ensure male germ cell development (reviewed in [64]. Initiation of meiosis in humans is at least in part dependent on the action of retinoic acid (RA) [27,[65][66], which induces expression of the pre-meiosis marker STRA8 [65][66].…”

Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

“…In this setting, PGCs, now termed gonocytes, begin to multiply rapidly. At 17–18 weeks of gestation, gonocytes begin to mature into pre-/fetal spermatogonia, a process involving down-regulation of pluripotency factors, gradual migration to the basal lamina of the sex cords, and a relative quiescence until after birth [10,11]. Following testicular descent at or around birth, a surge in testosterone production and other testicular hormones occurs [12].…”

Is the FSHR 2039A>G variant associated with susceptibility to testicular germ cell cancer?

“…TGCC is believed to arise from germ cell neoplasia in situ (GCNIS) cells (Skakkebaek et al, 1987;Albers et al, 2011;Rajpert-De Meyts et al, 2015;Moch et al, 2016), which are assumed to originate from foetal gonocytes that failed to develop into spermatogonia due to niche disturbances affecting the Sertoli cells (Rajpert-De Meyts et al, 2015). Little is known about the role of FSH activity for early germ cell differentiation, but there is a clear sexual difference in the foetal FSH levels with considerably lower levels in the male foetus compared to female (Clements et al, 1976) and it has previously been suggested that GCNIS cells may be 'sexually confused' by the inadequately virilized somatic niche during testis development (Jørgensen & Rajpert-De Meyts, 2014). FSH transiently increases during minipuberty, and there is some evidence that boys with cryptorchidism, a risk group for TGCC, have increased FSH levels already during this period (Suomi et al, 2006).…”