The stabilization of beta-catenin leads to impaired primordial germ cell development via aberrant cell cycle progression.
The stabilization of beta-catenin leads to impaired primordial germ cell development via aberrant cell cycle progression.
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发表时间：
2006
影响因子：
2.7
通讯作者：
Tohru Kimura;Toshinobu Nakamura;Kazushige Murayama;H. Umehara;Noriko Yamano;Shoko Watanabe;M. Taketo;T. Nakano
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文献类型：
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作者：
Tohru Kimura;Toshinobu Nakamura;Kazushige Murayama;H. Umehara;Noriko Yamano;Shoko Watanabe;M. Taketo;T. Nakano
原始生殖细胞（PGCs）是生殖细胞的前体细胞，致力于精子或卵母细胞。PGC发育过程中的急剧增殖决定了创始精原细胞和卵母细胞的数量。尽管PGCs被指定为生殖谱系，但PGCs在体外产生多能胚胎生殖（EG）细胞，在体内产生睾丸畸胎瘤。Wnt/β-连环蛋白信号传导调节各种干细胞系统中的多能性和分化，并且这种信号传导的失调导致各种人类癌症。在这里，我们研究了Wnt/β-catenin信号在PGC发展中的作用。在正常的PGC发展中，Wnt/β-连环蛋白信号传导被GSK 3 β介导的β-连环蛋白的主动降解和典型Wnt分子的低表达抑制。使用缺失编码β-连环蛋白基因座中GSK 3 β磷酸化位点的外显子的小鼠分析PGC中Wnt/β-连环蛋白信号传导异常激活的影响。尽管Wnt/β-连环蛋白信号传导在各种细胞谱系的干细胞维持和致癌作用中具有潜在活性，但在PGC中表达核定位β-连环蛋白的小鼠中并未诱导畸胎瘤。相反，突变小鼠表现出生殖细胞缺陷，这是由增殖期PGCs的细胞周期进展延迟引起的。我们的研究结果表明，Wnt/β-catenin信号的抑制是PGCs正常发育的先决条件。
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.