School of Medicine Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
School of Medicine Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA
Development. 2019 Aug 29;146(16):dev175604. doi: 10.1242/dev.175604.
WNT/β-catenin signaling is crucial for neural crest (NC) formation, yet the effects of the magnitude of the WNT signal remain ill-defined. Using a robust model of human NC formation based on human pluripotent stem cells (hPSCs), we expose that the WNT signal modulates the axial identity of NCs in a dose-dependent manner, with low WNT leading to anterior OTX HOX NC and high WNT leading to posterior OTX HOX NC. Differentiation tests of posterior NC confirm expected derivatives, including posterior-specific adrenal derivatives, and display partial capacity to generate anterior ectomesenchymal derivatives. Furthermore, unlike anterior NC, posterior NC exhibits a transient TBXT/SOX2 neuromesodermal precursor-like intermediate. Finally, we analyze the contributions of other signaling pathways in posterior NC formation, which suggest a crucial role for FGF in survival/proliferation, and a requirement of BMP for NC maturation. As expected retinoic acid (RA) and FGF are able to modulate HOX expression in the posterior NC. Surprisingly, early RA supplementation prohibits NC formation. This work reveals for the first time that the amplitude of WNT signaling can modulate the axial identity of NC cells in humans.
WNT/β-catenin 信号通路对于神经嵴（NC）的形成至关重要，但 WNT 信号的幅度的影响仍不清楚。我们使用基于人类多能干细胞（hPSC）的强大人类 NC 形成模型，发现 WNT 信号以剂量依赖的方式调节 NC 的轴向身份，低 WNT 导致前 OTX HOX NC，高 WNT 导致后 OTX HOX NC。对后 NC 的分化测试证实了预期的衍生物，包括后特定肾上腺衍生物，并显示出部分生成前外胚层衍生物的能力。此外，与前 NC 不同，后 NC 表现出短暂的 TBXT/SOX2 神经中胚层前体样中间状态。最后，我们分析了其他信号通路在后 NC 形成中的作用，这些结果表明 FGF 在生存/增殖中起着关键作用，而 BMP 对于 NC 成熟是必需的。如预期的那样，视黄酸（RA）和 FGF 能够调节后 NC 中的 HOX 表达。令人惊讶的是，早期 RA 补充会阻止 NC 的形成。这项工作首次揭示了 WNT 信号的幅度可以调节人类 NC 细胞的轴向身份。
