Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, predisposition to cancer and developmental defects including hypogonadism. Reproductive defects leading to germ cell aplasia are the most consistent phenotypes seen in FA mouse models. We examined the role of the nuclear FA core complex gene Fancg in the development of primordial germ cells (PGCs), the embryonic precursors of adult gametes, during fetal development. PGC maintenance was severely impaired in Fancg−/− embryos. We observed a defect in the number of PGCs starting at E9.5 and a strong attrition at E11.5 and E13.5. Remarkably, we observed a mosaic pattern reflecting a portion of testicular cords devoid of PGCs in E13.5 fetal gonads. Our in vitro and in vivo data highlight a potential role of Fancg in the proliferation and in the intrinsic cell motility abilities of PGCs. The random migratory process is abnormally activated in Fancg−/− PGCs, altering the migration of cells. Increased cell death and PGC attrition observed in E11.5 Fancg−/− embryos are features consistent with delayed migration of PGCs along the migratory pathway to the genital ridges. Moreover, we show that an inhibitor of RAC1 mitigates the abnormal migratory pattern observed in Fancg−/− PGCs.

中文翻译：

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与 Rac1 信号相关的异常迁移行为导致范可尼贫血通路缺陷型 Fancg-/- 胚胎的原始生殖细胞衰竭

范可尼贫血 (FA) 是一种罕见的人类遗传疾病，其特征是骨髓衰竭、易患癌症和发育缺陷，包括性腺机能减退。导致生殖细胞发育不全的生殖缺陷是在 FA 小鼠模型中观察到的最一致的表型。我们检查了核 FA 核心复合物基因 Fincg 在胎儿发育过程中在成体配子的胚胎前体原始生殖细胞 (PGC) 发育中的作用。Fincg-/-胚胎的PGC维持严重受损。我们观察到从 E9.5 开始的 PGC 数量存在缺陷，并且在 E11.5 和 E13.5 出现了强烈的减员。值得注意的是，我们观察到马赛克图案反映了 E13.5 胎儿性腺中没有 PGC 的一部分睾丸索。我们的体外和体内数据强调了 Fancg 在 PGC 的增殖和内在细胞运动能力中的潜在作用。Fancg-/- PGC 中的随机迁移过程异常激活，从而改变了细胞的迁移。在 E11.5 Fancg - / - 胚胎中观察到的细胞死亡和 PGC 磨损增加是与 PGC 沿迁移途径延迟迁移到生殖脊的特征一致。此外，我们表明 RAC1 抑制剂减轻了在 Fancg-/- PGC 中观察到的异常迁移模式。