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Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25677-25687. doi: 10.1073/pnas.1910733116. Epub 2019 Nov 21.

Mammalian germ cells are determined after PGC colonization of the nascent gonad.

Author information

1
Whitehead Institute, Cambridge, MA 02142.
2
Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany.
3
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
4
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
5
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
6
Reproductive Medicine Center, Sixth Affiliated Hospital, Sun Yat-sen University, 510655 Guangzhou, China.
7
Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
8
Recombinetics, Inc., Saint Paul, MN 55104.
9
Whitehead Institute, Cambridge, MA 02142; dcpage@wi.mit.edu.
10
Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142.

Abstract

Mammalian primordial germ cells (PGCs) are induced in the embryonic epiblast, before migrating to the nascent gonads. In fish, frogs, and birds, the germline segregates even earlier, through the action of maternally inherited germ plasm. Across vertebrates, migrating PGCs retain a broad developmental potential, regardless of whether they were induced or maternally segregated. In mammals, this potential is indicated by expression of pluripotency factors, and the ability to generate teratomas and pluripotent cell lines. How the germline loses this developmental potential remains unknown. Our genome-wide analyses of embryonic human and mouse germlines reveal a conserved transcriptional program, initiated in PGCs after gonadal colonization, that differentiates germ cells from their germline precursors and from somatic lineages. Through genetic studies in mice and pigs, we demonstrate that one such gonad-induced factor, the RNA-binding protein DAZL, is necessary in vivo to restrict the developmental potential of the germline; DAZL's absence prolongs expression of a Nanog pluripotency reporter, facilitates derivation of pluripotent cell lines, and causes spontaneous gonadal teratomas. Based on these observations in humans, mice, and pigs, we propose that germ cells are determined after gonadal colonization in mammals. We suggest that germ cell determination was induced late in embryogenesis-after organogenesis has begun-in the common ancestor of all vertebrates, as in modern mammals, where this transition is induced by somatic cells of the gonad. We suggest that failure of this process of germ cell determination likely accounts for the origin of human testis cancer.

KEYWORDS:

Dazl; commitment; germ cell; pluripotency; teratoma

PMID:
31754036
PMCID:
PMC6925976
[Available on 2020-05-21]
DOI:
10.1073/pnas.1910733116

Conflict of interest statement

Competing interest statement: A.L.W., D.F.C., and S.C.F. are employees and shareholders of Recombinetics Inc. I.D. is a member of the scientific advisory board of Recombinetics Inc. The remaining authors have declared that no competing interests exist.

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