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Principles of early human development and germ cell program from observed model systems

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Kobayashi, T 
Zhang, H 
Tang, WC 
Irie, N 
Withey, S 

Abstract

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during weeks 2–3 of early post-implantation development1. Using in vitro models of hPGC induction2,3,4, recent studies have suggested that there are marked mechanistic differences in the specification of human and mouse PGCs5. This may be due in part to the divergence in their pluripotency networks and early post-implantation development6,7,8. As early human embryos are not accessible for direct study, we considered alternatives including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs originate from the posterior pre-primitive-streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. We use this model together with human and monkey in vitro models simulating peri-gastrulation development to show the conserved principles of epiblast development for competency for primordial germ cell fate. This process is followed by initiation of the epigenetic program9,10,11 and regulated by a balanced SOX17–BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models provides synthetic insights into early human development.

Description

Keywords

Animals, Bone Morphogenetic Proteins, Cell Differentiation, Cell Lineage, Embryoid Bodies, Embryonic Development, Epigenesis, Genetic, Female, Gastrulation, Gene Dosage, Germ Cells, Germ Layers, Humans, In Vitro Techniques, Macaca fascicularis, Male, Models, Animal, Models, Biological, Pluripotent Stem Cells, Positive Regulatory Domain I-Binding Factor 1, Primitive Streak, Repressor Proteins, SOXF Transcription Factors, Swine, Wnt Signaling Pathway

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

546

Publisher

Nature Publishing Group
Sponsorship
Wellcome Trust (096738/Z/11/Z)
Biotechnology and Biological Sciences Research Council (BB/M001466/1)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/P009948/1)
Wellcome Trust Medical Research Council BBSRC