A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants

Shinya Aramaki; Katsuhiko Hayashi; Kazuki Kurimoto; Hiroshi Ohta; Yukihiro Yabuta; Hiroko Iwanari; Yasuhiro Mochizuki; Takao Hamakubo; Yuki Kato; Katsuhiko Shirahige; Mitinori Saitou

doi:10.1016/j.devcel.2013.11.001

A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants

Dev Cell. 2013 Dec 9;27(5):516-29. doi: 10.1016/j.devcel.2013.11.001.

Affiliations

¹ Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
² Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.
³ Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
⁴ Laboratory of Genome Structure and Function, Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: saitou@anat2.med.kyoto-u.ac.jp.

PMID: 24331926
DOI: 10.1016/j.devcel.2013.11.001

Abstract

Germ cells ensure reproduction and heredity. In mice, primordial germ cells (PGCs), the precursors for spermatozoa and oocytes, are induced in pluripotent epiblast by BMP4 and WNT3, yet the underlying mechanism remains unclear. Here, using an in vitro PGC specification system, we show that WNT3 induces many transcription factors associated with mesoderm in epiblast-like cells through β-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14 and directly upregulates these genes, delineating the downstream PGC program. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating a permissive role of BMP4 in PGC specification. These findings establish the key signaling mechanism for, and a fundamental role of a mesodermal factor in, mammalian PGC specification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blastocyst / cytology
Bone Morphogenetic Protein 4 / metabolism
DNA-Binding Proteins
Embryonic Stem Cells / cytology*
Embryonic Stem Cells / metabolism*
Epigenesis, Genetic / physiology
Female
Fetal Proteins / genetics
Fetal Proteins / metabolism*
Gene Expression Regulation, Developmental
Germ Cells / cytology*
Germ Cells / metabolism*
Male
Mesoderm / cytology
Mesoderm / metabolism
Mice, Mutant Strains
Positive Regulatory Domain I-Binding Factor 1
Pregnancy
RNA-Binding Proteins
Signal Transduction / physiology
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism*
Transcription Factors / metabolism
Wnt3 Protein / metabolism
beta Catenin / metabolism

Substances

Bmp4 protein, mouse
Bone Morphogenetic Protein 4
CTNNB1 protein, mouse
DNA-Binding Proteins
Fetal Proteins
Prdm1 protein, mouse
Prdm14 protein, mouse
RNA-Binding Proteins
T-Box Domain Proteins
Transcription Factors
Wnt3 Protein
Wnt3 protein, mouse
beta Catenin
Positive Regulatory Domain I-Binding Factor 1
Brachyury protein

Associated data

GEO/GSE49689
GEO/GSE50394