title: Persistent Requirement and Alteration of the Key Targets of PRDM1 During Primordial Germ Cell Development in Mice.
abstract: Primordial germ cells (PGCs) are the foundation of totipotency and vital for reproduction and heredity. PGCs in mice arise from the epiblast around Embryonic Day (E) 7.0, migrate through the hindgut endoderm, and colonize and proliferate in the embryonic gonads until around E13.5 prior to their differentiation either into prospermatogonia or oogonia. PRDM1, a transcriptional repressor, plays an essential role in PGC specification that includes robustly repressing a somatic mesodermal program. Using an inducible conditional knockout system, we show here that PRDM1 is critically required throughout PGC development. When Prdm1 was deleted in migrating PGCs at E9.5 or E10.5, or in male gonadal PGCs at E11.5, PGCs were eliminated by apoptosis from around E10.5, E11.5, or E13.5, respectively. When Prdm1 was deleted in female gonadal PGCs at E11.5, PGCs progressed into the first meiotic prophase in an apparently normal fashion, but the oogonia exhibited an aberrant pachytene phenotype, undergoing abrupt apoptosis from around E16.5. The escape of a fraction of PGCs (∼10%) from the Prdm1 deletion was sufficient to recover fairly normal germ cell pools, both in male and female adults. The key targets of PRDM1 in migrating and/or gonadal PGCs, including genes for development, apoptosis, and prospermatogonial differentiation, showed only a modest overlap with those upon PGC specification, and were enriched with histone H3 lysine 27 trimethylation (H3K27me3). Our findings provide critical insight into the mechanism for maintaining the transcriptional integrity of PGCs.
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Yamashiro
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hirota
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kurimoto
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yabuta
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: So I
authors.initials: SI
authors.lastname: Nagaoka
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan JST, Agency for Medical Research and Development (AMED) - Core Research for Evolutional Science and Technology (CREST), Saitama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, Japan Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan saitou@anat2.med.kyoto-u.ac.jp.
authors.forename: Mitinori
authors.initials: M
authors.lastname: Saitou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D005854:Germ Cells / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D018345:Mice, Knockout; D009867:Oogonia / Q000378:metabolism; D010053:Ovary / Q000196:embryology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011247:Pregnancy; D013737:Testis / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
chemical_list: D006657:Histones; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: apoptosis; primordial germ cells; transcriptional repression; transgenic/knockout model