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Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2017-10-05 , DOI: 10.1016/j.stem.2017.09.005
Yoji Kojima , Kotaro Sasaki , Shihori Yokobayashi , Yoshitake Sakai , Tomonori Nakamura , Yukihiro Yabuta , Fumio Nakaki , So Nagaoka , Knut Woltjen , Akitsu Hotta , Takuya Yamamoto , Mitinori Saitou

Germline specification underlies human reproduction and evolution, but it has proven difficult to study in humans since it occurs shortly after blastocyst implantation. This process can be modeled with human induced pluripotent stem cells (hiPSCs) by differentiating them into primordial germ cell-like cells (hPGCLCs) through an incipient mesoderm-like cell (iMeLC) state. Here, we elucidate the key transcription factors and their interactions with important signaling pathways in driving hPGCLC differentiation from iPSCs. Germline competence of iMeLCs is dictated by the duration and dosage of WNT signaling, which induces expression of EOMES to activate SOX17, a key driver of hPGCLC specification. Upon hPGCLC induction, BMP signaling activates TFAP2C in a SOX17-independent manner. SOX17 and TFAP2C then cooperatively instate an hPGCLC transcriptional program, including BLIMP1 expression. This specification program diverges from its mouse counterpart regarding key transcription factors and their hierarchies, and it provides a foundation for further study of human germ cell development.

中文翻译:

进化上独特的转录和信号传导程序从多能干细胞驱动人类生殖细胞谱系规范。

胚系规格是人类繁殖和进化的基础,但由于在胚泡植入后不久就发生,因此已证明难以在人体中研究。可以通过人诱导的多能干细胞(hiPSC)通过初始中胚层样细胞(iMeLC)分化为原始生殖细胞样细胞(hPGCLC)来模拟此过程。在这里,我们阐明了关键的转录因子及其与重要的信号通路的相互作用,以驱动hPGCLC从iPSC分化。iMeLC的种系能力由WNT信号传导的持续时间和剂量决定,WNT信号传导诱导EOMES的表达激活hPGCLC规范的关键驱动力SOX17。在hPGCLC诱导后,BMP信号以SOX17独立的方式激活TFAP2C。然后,SOX17和TFAP2C协同建立hPGCLC转录程序,包括BLIMP1表达。该规范程序在关键转录因子及其层次结构上与它的小鼠相对应不同,它为进一步研究人类生殖细胞提供了基础。
更新日期:2017-10-05
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