The Germ Cell Fate of Cynomolgus Monkeys Is Specified in the Nascent Amnion

Abstract

The germ cell lineage ensures reproduction and heredity. The mechanism for germ cell specification in primates, including humans, has remained unknown. In primates, upon implantation the pluripotent epiblast segregates the amnion, an extra-embryonic membrane eventually ensheathing an embryo, and thereafter initiates gastrulation to generate three germ layers. Here, we show that in cynomolgus monkeys, the SOX17/TFAP2C/BLIMP1-positive primordial germ cells (cyPGCs) originate from the dorsal amnion at embryonic day 11 (E11) prior to gastrulation. cyPGCs appear to migrate down the amnion and, through proliferation and recruitment from the posterior amnion, expand in number around the posterior yolk sac by E17. Remarkably, the amnion itself expresses BMP4 and WNT3A, cytokines potentially critical for cyPGC specification, and responds primarily to them. Moreover, human PGC-like cells in vitro exhibit a transcriptome similar to cyPGCs just after specification. Our study identifies the origin of PGCs and a unique function of the nascent amnion in primates.

On the origin of the human germline

“…In line with these well-established signalling principles, we found that porcine PGCs are specified at the posterior epiblast at the early primitive streak stage, suggesting the posterior epiblast has an appropriate environment for PGC induction . However, a recent study of cynomolgus monkey embryos has indicated that nascent PGCs can emerge from the early amnion, which is an extra-embryonic membrane structure that subsequently surrounds the fetus (Sasaki et al, 2016). In primates, including humans, the amnion is formed from the pluripotent epiblast soon after implantation, albeit at a different time; this is not the case in pig and other mammalian embryos, in which the amnion develops after the initiation of gastrulation (Hassoun et al, 2010).…”

“…In primates, including humans, the amnion is formed from the pluripotent epiblast soon after implantation, albeit at a different time; this is not the case in pig and other mammalian embryos, in which the amnion develops after the initiation of gastrulation (Hassoun et al, 2010). In monkey embryos, WNT is expressed in the cytotrophoblast layer relatively close to the amnion, whereas the amnion itself is a source of BMP, indicating that there is an appropriate environment in this tissue for PGC specification (Sasaki et al, 2016). Regardless, the question of whether PGCs originate exclusively from the amnion in primates still remains unanswered.…”

“…Furthermore, expression of KLF4, a naïve pluripotency factor, in hPGCs is noteworthy, as KLF4 is repressed in mPGCs by BLIMP1 (DurcovaHills et al, 2008;Hackett et al, 2017). Interestingly, germ cells in pig and monkey embryos, which similarly develop as bilaminar discs, also share these characteristics of the human germline Sasaki et al, 2016). Even in basal Hystricognathi rodents, Lagostomus maximus, which surprisingly develop as flat-bilaminar discs, PGCs show expression of SOX17 and absence of SOX2 expression (Leopardo and Vitullo, 2017).…”

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“…The mechanisms of symmetry breaking leading to AP axis formation in human embryos remain unknown, but mechanical and chemical cues are clearly involved. In cynomolgus monkey embryos, a population of hypoblast cells that expresses Wnt and Nodal inhibitors (DKK1 and CER1), characteristic of the mouse AVE, has been identified (15). Is a dialogue between mother and embryo required for this morphogenesis?…”

“…This treatment induces the patches to fold into closed polarized shells, which, depending on the initial cell density, can generate squamous, asymmetric, or columnar cysts. Squamous cysts represent an amnion-like tissue based on gene expression, cell shape, and BMP signaling activity (51), also active in the amnion of cynomolgous monkeys (15). Columnar cysts represent the epiblast, and asymmetric cysts undergo a symmetry-breaking event to form an amnion-like hemisphere and an epithelia-like disc (Figs.…”