College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
Sci Rep. 2022 Aug 30;12(1):14726. doi: 10.1038/s41598-022-19029-3.
Early embryonic development of the spinal cord requires tight coordination between proliferation of neural progenitors and their differentiation into distinct neuronal cell types to establish intricate neuronal circuits. The Hippo pathway is one of the well-known regulators to control cell proliferation and govern neural progenitor cell number, in which the downstream effector Yes-associated protein (Yap) promotes cell cycle progression. Here we show that an atypical cadherin Fat3, expressed highly in the neural tube, plays a critical role in maintaining proper number of proliferating progenitors. Knockdown of Fat3 in chick neural tube down-regulates expression of the proliferation markers but rather induces the expression of neural markers in the ventricular zone. We further show that deletion of Fat3 gene in mouse neural tube depletes neural progenitors, accompanied by neuronal gene expression in the ventral ventricular zone of the spinal cord. Finally, we found that Fat3 regulates the phosphorylation level of Lats1/2, the upstream kinase of Yap, resulting in dephosphorylation and stabilization of Yap, suggesting Yap as a key downstream effector of Fat3. Our study uncovers another layer of regulatory mechanisms in controlling the activity of Hippo signaling pathway to regulate the size of neural progenitor pools in the developing spinal cord.
脊髓的早期胚胎发育需要神经祖细胞的增殖与其分化为不同的神经元细胞类型之间的紧密协调，以建立复杂的神经元回路。Hippo 通路是控制细胞增殖和调节神经祖细胞数量的著名调节因子之一，其下游效应物 Yes 相关蛋白（Yap）促进细胞周期进程。在这里，我们发现高度表达于神经管中的非典型钙黏蛋白 Fat3 在维持适当数量的增殖祖细胞方面起着关键作用。在鸡神经管中敲低 Fat3 会下调增殖标记物的表达，但会在脑室区诱导神经标记物的表达。我们进一步表明，在小鼠神经管中删除 Fat3 基因会耗尽神经祖细胞，伴随着脊髓腹侧脑室区神经元基因的表达。最后，我们发现 Fat3 调节 Yap 的上游激酶 Lats1/2 的磷酸化水平，导致 Yap 的去磷酸化和稳定，表明 Yap 是 Fat3 的关键下游效应物。我们的研究揭示了控制 Hippo 信号通路活性的另一个调控机制，以调节发育中脊髓中神经祖细胞库的大小。
