原始生殖细胞的指定
中文名称
通路描述
原始生殖细胞 (PGCs) 是雌性配子 (卵母细胞) 和雄性配子 (精子) 的 progenitor，在哺乳动物发育早期从体细胞中指定和分离。在小鼠胚胎中，PGC 的前体存在于胚胎近端外胚层，位于额外胚胎外胚层之前，在囊胚期 (E6.0，预条纹阶段) 存在。PGC 在胚胎发育过程中通过额外胚胎外胚层底部发育全胚叶的基部转移到额外胚胎中胚层，并标记为高碱性磷酸酶活性 (Ginsburg et al. 1990)。随后，PGC 在胚胎肠上皮中区域化，并通过胚胎肠的背侧中胚层迁移到生殖嵴。迁移后的 PGC 在胎儿生殖腺中分化为卵母细胞和精原细胞。在小鼠胚胎中，PGC 由额外胚胎外胚层发出的 Bmp4 和腹膜内胚层发出的 Wnt3 诱导 (reviewed in Bleckwehl and Rada Iglesias 2019)。关于人类 PGC 的发育起源知之甚少，诱导信号因子的来源也是如此。在非人灵长类动物 (恒河猴) 中，PGC 在囊胚的囊胚上皮中首次观察到，并在早期羊膜囊中停留较长时间 (6 天) (Sasaki et al. 2016)。BMP4 在羊膜中表达，WNT3A 在滋养层细胞中表达 (Sasaki et al. 2016)。体外和细胞培养研究已进行以阐明人类 PGC 的指定 (reviewed in Hancock et al. 2021)。通过免疫荧光鉴定 PGC 标记物的拟态 PGC 在早期囊胚 (E6 天受精后，dpf) 的体外培养中诱导 (Chen et al. 2019, Popovic et al. 2019)，以及在胚胎干细胞 (ESCs) 或诱导多能干细胞 (iPSCs) 的体外分化中，在 BMP4 存在下 (Irie et al. 2015, Sasaki et al. 2015, Tang et al. 2015, Chen et al. 2017, Kojima et al. 2017)。在小鼠胚胎和细胞培养的人类细胞中，在 BMP4 信号存在下形成 PGC 的胚胎外胚层样细胞的潜能是短暂的，其中，在没有 BMP4 的情况下，胚胎外胚层样细胞获得中胚层细胞命运 (Tang et al. 2015)。从人类多能干细胞诱导 PGC 样细胞，指定人类 PGC 的基因网络活性与小鼠 PGC 不同。值得注意的是，SOX17 不是 Prdm14，而是人类 PGC 指定的关键因素。在人类 PGC 前体中，Eomesodermin (EOMES) 激活 SOX17 的表达，SOX17 是 PGC 指定的最上游因素。在人类胚胎和恒河猴早期 PGC 中观察到类似的分子事件。BMP4 信号启动 TFAP2C 和 SOX17 的表达，进而启动 PRDM1 的表达 (Tang et al. 2015, Kojima et al. 2017, Tang et al. 2022)。这三个关键因素 SOX17、TFAP2C 和 PRDM1 指定 PGC，激活 PGC 程序，并抑制体细胞程序，其中 SOX17 作为激活因子，PRDM1 作为抑制因子 (Tang et al. 2015, Sasaki et al. 2015)。在 PGC 中激活的基因包括与多能性相关的因素 POU5F1 (OCT4) 和 NANOG (但不包括 SOX2)、DNA 去甲基化因子 TET2 以及细胞迁移调节因子 PDPN 和 CXCR4 (Irie et al. 2015, Sasaki et al. 2015, Chen et al. 2018, Mishra et al. 2021, Tang et al. 2022)。PRDM1 抑制与 DNA 甲基化相关的基因，导致人类 PGC 在发育第 10-11 周左右的全基因组 DNA 去甲基化 (Guo et al. 2015)。在小鼠胚胎癌细胞中，Prdm1 (Blimp1) 结合并抑制去 novo DNA 甲基化酶 Dnmt3b 和 Uhrf1 的表达，后者与 DNA 甲基化酶 Dnmt1 相互作用 (Magnusdottir et al. 2013)。PRDM1 在人类 PGC 中通过尚未表征的机制抑制 DNMT3B、DNMT1 和 UHRF1 的表达 (Tang et al. 2015)。
英文描述
Specification of primordial germ cells Primordial germ cells (PGCs), the progenitors of female gametes (oocytes) and male gametes (sperm), are specified and segregated from somatic cells early during mammalian development. In the mouse embryo, precursors of PGCs are present in the proximal epiblast adjacent to the extraembryonic ectoderm before gastrulation (E6.0, pre-streak stage) and PGCs, marked by high alkaline phosphatase activity (Ginsburg et al. 1990), are translocated to the extraembryonic mesoderm at the base of the developing allantois during gastrulation (Lawson and Hage 1994). Subsequently, PGCs are regionalised in the epithelium of the embryonic gut and migrate via the dorsal mesentery of the embryonic gut to the genital ridge. The post-migratory PGCs differentiate into oogonia and spermatogonia in the fetal gonad. In mouse embryos, PGCs are induced by Bmp4 emanating from extraembryonic ectoderm and Wnt3 from the visceral endoderm (reviewed in Bleckwehl and Rada Iglesias 2019). Less is known about the developmental origin of human PGCs and the sources of inducing signaling factors. In the non human primate (Cynomolgus monkey), PGCs are first observed in the amniotic epithelium of the amniotic sac of the pre-gastrulation embryo and remain in the early amnion for an extended period (6 days) (Sasaki et al. 2016). BMP4 is expressed in the amnion and WNT3A is expressed in the cytotrophoblast (Sasaki et al. 2016).
Ex vivo and in vitro studies have been performed to elucidate the specification of human PGCs (reviewed in Hancock et al. 2021). Putative PGCs, identified by immunofluorescence of PGC markers, are induced in ex vivo culture of early blastocysts (E6 days post fertilization, dpf) (Chen et al. 2019, Popovic et al. 2019) and in vitro differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in the presence of BMP4 (Irie et al. 2015, Sasaki et al. 2015, Tang et al. 2015, Chen et al. 2017, Kojima et al. 2017). In both mouse embryos and cultured human cells, competence of the epiblast-like cells to form PGCs in response to BMP4 signals is transient during development, where, in the absence of BMP4, the epiblast-like cells acquire the mesendoderm cell fate (Tang et al. 2015).
For the induction of PGC-like cells from human pluripotent stem cells, the gene network activity that specifies human PGCs is different from that of mouse PGCs. Notably, SOX17, but not Prdm14, is a key factor for the specification of human PGCs. In human PGC precursors, Eomesodermin (EOMES) activates expression of SOX17, the most upstream factor in PGC specification. Similar molecular events are observed in the early PGCs isolated from human embryos and cynomolgus monkeys (Tyser et al. 2021). BMP4 signaling initiates the expression of TFAP2C and SOX17, that in turns initiates expression of PRDM1 (Tang et al. 2015, Kojima et al. 2017, Tang et al. 2022). Together these three key factors, SOX17, TFAP2C, and PRDM1, specify PGCs, activate the PGC program, and repress somatic cell programs, with SOX17 acting as an activator and PRDM1 as a repressor (Tang et al. 2015, Sasaki et al. 2015). Genes activated in PGCs include the pluripotency-related factors POU5F1 (OCT4) and NANOG (but not SOX2), the DNA demethylation factor TET2, and the regulators of cell migration PDPN and CXCR4 (Irie et al. 2015, Sasaki et al. 2015, Chen et al. 2018, Mishra et al. 2021, Tang et al. 2022). PRDM1 represses genes involved in DNA methylation leading to a genome wide DNA demethylation in human PGCs around week 10-11 of development (Guo et al. 2015). In mouse embryonal carcinoma cells, Prdm1 (Blimp1) binds and represses expression of the de novo DNA methylase Dnmt3b and Uhrf1, which interacts with the DNA methylase Dnmt1 (Magnusdottir et al. 2013). PRDM1 in human PGCs similarly represses expression of DNMT3B, DNMT1, and UHRF1 through yet uncharacterized mechanisms (Tang et al. 2015).
Ex vivo and in vitro studies have been performed to elucidate the specification of human PGCs (reviewed in Hancock et al. 2021). Putative PGCs, identified by immunofluorescence of PGC markers, are induced in ex vivo culture of early blastocysts (E6 days post fertilization, dpf) (Chen et al. 2019, Popovic et al. 2019) and in vitro differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in the presence of BMP4 (Irie et al. 2015, Sasaki et al. 2015, Tang et al. 2015, Chen et al. 2017, Kojima et al. 2017). In both mouse embryos and cultured human cells, competence of the epiblast-like cells to form PGCs in response to BMP4 signals is transient during development, where, in the absence of BMP4, the epiblast-like cells acquire the mesendoderm cell fate (Tang et al. 2015).
For the induction of PGC-like cells from human pluripotent stem cells, the gene network activity that specifies human PGCs is different from that of mouse PGCs. Notably, SOX17, but not Prdm14, is a key factor for the specification of human PGCs. In human PGC precursors, Eomesodermin (EOMES) activates expression of SOX17, the most upstream factor in PGC specification. Similar molecular events are observed in the early PGCs isolated from human embryos and cynomolgus monkeys (Tyser et al. 2021). BMP4 signaling initiates the expression of TFAP2C and SOX17, that in turns initiates expression of PRDM1 (Tang et al. 2015, Kojima et al. 2017, Tang et al. 2022). Together these three key factors, SOX17, TFAP2C, and PRDM1, specify PGCs, activate the PGC program, and repress somatic cell programs, with SOX17 acting as an activator and PRDM1 as a repressor (Tang et al. 2015, Sasaki et al. 2015). Genes activated in PGCs include the pluripotency-related factors POU5F1 (OCT4) and NANOG (but not SOX2), the DNA demethylation factor TET2, and the regulators of cell migration PDPN and CXCR4 (Irie et al. 2015, Sasaki et al. 2015, Chen et al. 2018, Mishra et al. 2021, Tang et al. 2022). PRDM1 represses genes involved in DNA methylation leading to a genome wide DNA demethylation in human PGCs around week 10-11 of development (Guo et al. 2015). In mouse embryonal carcinoma cells, Prdm1 (Blimp1) binds and represses expression of the de novo DNA methylase Dnmt3b and Uhrf1, which interacts with the DNA methylase Dnmt1 (Magnusdottir et al. 2013). PRDM1 in human PGCs similarly represses expression of DNMT3B, DNMT1, and UHRF1 through yet uncharacterized mechanisms (Tang et al. 2015).
所含基因
12 个基因