A PAX5-OCT4-PRDM1 developmental switch specifies human primordial germ cells
Fang Fang, Benjamin Angulo, Ninuo Xia, Meena Sukhwani, Zhengyuan Wang, Charles C. Carey, Aurelien Mazurie, Jun Cui, Royce Wilkinson, Blake Wiedenheft, Naoko Irie, M. Azim Surani, Kyle E. Orwig, Renee A. Reijo Pera
Nature Cell Biology
Dysregulation of genetic pathways during human germ cell development leads to infertility. Here, we analysed bona fide human primordial germ cells (hPGCs) to probe the developmental genetics of human germ cell specification and differentiation. We examined the distribution of OCT4 occupancy in hPGCs relative to human embryonic stem cells (hESCs). We demonstrated that development, from pluripotent stem cells to germ cells, is driven by switching partners with OCT4 from SOX2 to PAX5 and PRDM1. Gain- and loss-of-function studies revealed that PAX5 encodes a critical regulator of hPGC development. Moreover, an epistasis analysis indicated that PAX5 acts upstream of OCT4 and PRDM1. The PAX5-OCT4-PRDM1 proteins form a core transcriptional network that activates germline and represses somatic programmes during human germ cell differentiation. These findings illustrate the power of combined genome editing, cell differentiation and engraftment for probing human developmental genetics that have historically been difficult to study.
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