Ob/Gyn Department, Center for Reproductive Sciences, University of California San Francisco, CA, USA.
PLoS Genet. 2011 Dec;7(12):e1002428. doi: 10.1371/journal.pgen.1002428. Epub 2011 Dec 22.
The trafficking of primordial germ cells (PGCs) across multiple embryonic structures to the nascent gonads ensures the transmission of genetic information to the next generation through the gametes, yet our understanding of the mechanisms underlying PGC migration remains incomplete. Here we identify a role for the receptor tyrosine kinase-like protein Ror2 in PGC development. In a Ror2 mouse mutant we isolated in a genetic screen, PGC migration and survival are dysregulated, resulting in a diminished number of PGCs in the embryonic gonad. A similar phenotype in Wnt5a mutants suggests that Wnt5a acts as a ligand to Ror2 in PGCs, although we do not find evidence that WNT5A functions as a PGC chemoattractant. We show that cultured PGCs undergo polarization, elongation, and reorientation in response to the chemotactic factor SCF (secreted KitL), whereas Ror2 PGCs are deficient in these SCF-induced responses. In the embryo, migratory PGCs exhibit a similar elongated geometry, whereas their counterparts in Ror2 mutants are round. The protein distribution of ROR2 within PGCs is asymmetric, both in vitro and in vivo; however, this asymmetry is lost in Ror2 mutants. Together these results indicate that Ror2 acts autonomously to permit the polarized response of PGCs to KitL. We propose a model by which Wnt5a potentiates PGC chemotaxis toward secreted KitL by redistribution of Ror2 within the cell.
原始生殖细胞 (PGC) 在多个胚胎结构中迁移到新生性腺,以确保通过配子将遗传信息传递给下一代,但我们对 PGC 迁移的机制的理解仍然不完整。在这里,我们确定了受体酪氨酸激酶样蛋白 Ror2 在 PGC 发育中的作用。在我们在遗传筛选中分离出的 Ror2 小鼠突变体中,PGC 的迁移和存活受到干扰,导致胚胎性腺中的 PGC 数量减少。Wnt5a 突变体中的类似表型表明 Wnt5a 作为配体在 PGC 中作用于 Ror2,尽管我们没有发现 WNT5A 作为 PGC 趋化因子的功能证据。我们表明,培养的 PGC 在响应趋化因子因子 SCF(分泌的 KitL)时会发生极化、伸长和重定向,而 Ror2 PGC 则缺乏这些 SCF 诱导的反应。在胚胎中,迁移的 PGC 表现出类似的伸长几何形状,而其在 Ror2 突变体中的对应物则是圆形的。ROR2 在 PGC 中的蛋白分布是不对称的,无论是在体外还是在体内;然而,这种不对称性在 Ror2 突变体中丢失。这些结果表明,Ror2 自主作用,允许 PGC 对 KitL 的极化反应。我们提出了一个模型,即 Wnt5a 通过在细胞内重新分配 Ror2 来增强 PGC 对分泌的 KitL 的趋化性。
PLoS Genet. 2011-12-22
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