title: REST and its downstream molecule Mek5 regulate survival of primordial germ cells.
abstract: In mouse embryos, some primordial germ cells (PGCs) are eliminated by apoptosis, but the molecular pathways that lead to PGC survival versus apoptosis have not been fully characterized. Here, we found that REST (repressor element 1-silencing transcription factor), a transcription factor that binds a conserved regulatory element, NRSE/RE1, played a role in PGC survival. REST expression was higher in PGCs than in surrounding somatic cells. Moreover, in mouse embryos with a PGC-specific conditional REST mutation, the PGC population experienced more apoptosis and was significantly smaller than that in control embryos; these findings indicated that REST functioned in a cell-autonomous fashion that was critical for PGC survival. Several anti-apoptotic genes were among the previously identified REST-target gene candidates; moreover, some of these genes were downregulated in the REST-deficient PGCs. Mek5, which encodes a component in the a MAP kinase cascade, was one of these downregulated REST-target gene candidates, and a Mek5 mutation, like the REST mutation, caused an increase in PGC apoptosis; these finding suggested that REST promoted PGC survival via regulation of the Mek5 expression. Importantly, there were a normal number of PGCs in the REST mutants at birth, and both the male and female REST-mutant adults were fertile; these final observations revealed that the PGC population was very robust and could recover from a genetically induced reduction in cell number.
authors.affiliation: Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Daiji
authors.initials: D
authors.lastname: Okamura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mochizuki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tokitake
authors.forename: Makiko
authors.initials: M
authors.lastname: Ikeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Cathy
authors.initials: C
authors.lastname: Tournier
authors.forename: Shinpei
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Tada
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Matsui
mesh_terms: D000818:Animals; D002470:Cell Survival; D018920:Coculture Techniques; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D048671:MAP Kinase Kinase 5; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C578399:Map2k5 protein, mouse