The stabilization of beta-catenin leads to impaired primordial germ cell development via aberrant cell cycle progression.
Primordial germ cells (PGCs) are germ cell precursors that are committed to sperm or oocytes. Dramatic proliferation during PGC development determines the number of founder spermatogonia and oocytes. Although specified to a germ lineage, PGCs produce pluripotent embryonic germ (EG) cells in vitro and testicular teratomas in vivo. Wnt/beta-catenin signaling regulates pluripotency and differentiation in various stem cell systems, and dysregulation of this signaling causes various human cancers. Here, we examined the role of Wnt/beta-catenin signaling in PGC development. In normal PGC development, Wnt/beta-catenin signaling is suppressed by the GSK3beta-mediated active degradation of beta-catenin and the low expression of canonical Wnt molecules. The effects of aberrant activation of Wnt/beta-catenin signaling in PGCs were analyzed using mice carrying a deletion of the exon that encodes the GSK3beta phosphorylation sites in the beta-catenin locus. Despite the potential activity of Wnt/beta-catenin signaling in stem cell maintenance and carcinogenesis in various cell lineages, teratomas were not induced in the mice expressing the nuclear-localized beta-catenin in PGCs. Instead, the mutant mice showed germ cell deficiency caused by the delayed cell cycle progression of the proliferative phase PGCs. Our results show that the suppression of Wnt/beta-catenin signaling is a prerequisite for the normal development of PGCs.
Kimura
Tohru
T
Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nakamura
Toshinobu
T
Murayama
Kazushige
K
Umehara
Hiroki
H
Yamano
Noriko
N
Watanabe
Shoko
S
Taketo
Makoto M
MM
Nakano
Toru
T
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D005260:Female; D005854:Germ Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000378:metabolism*; D009866:Oogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013091:Spermatogenesis / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism* / Q000502:physiology
D051176:beta Catenin