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Nat Cell Biol. 2018 Jun;20(6):655-665. doi: 10.1038/s41556-018-0094-3. Epub 2018 Apr 30.

A PAX5-OCT4-PRDM1 developmental switch specifies human primordial germ cells.

Author information

1
Department of Cell Biology and Neurosciences, Montana State University, Bozeman, MT, USA. fangfang0724@gmail.com.
2
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA. fangfang0724@gmail.com.
3
Department of Cell Biology and Neurosciences, Montana State University, Bozeman, MT, USA.
4
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA.
5
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, School of Medicine, Magee Women's Research Institute, Pittsburgh, PA, USA.
6
Genomic Medicine Division, Hematology Branch, NHLBI/NIH, Rockville, MD, USA.
7
Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA.
8
Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.

Abstract

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.

PMID:
29713018
PMCID:
PMC5970969
DOI:
10.1038/s41556-018-0094-3
[Indexed for MEDLINE]
Free PMC Article

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