Wang Jun, Xiao Yang, Hsu Chih-Wei, Martinez-Traverso Idaliz M, Zhang Min, Bai Yan, Ishii Mamoru, Maxson Robert E, Olson Eric N, Dickinson Mary E, Wythe Joshua D, Martin James F
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Development. 2016 Feb 1;143(3):504-15. doi: 10.1242/dev.126920. Epub 2015 Dec 30.
The role of the Hippo signaling pathway in cranial neural crest (CNC) development is poorly understood. We used the Wnt1(Cre) and Wnt1(Cre2SOR) drivers to conditionally ablate both Yap and Taz in the CNC of mice. When using either Cre driver, Yap and Taz deficiency in the CNC resulted in enlarged, hemorrhaging branchial arch blood vessels and hydrocephalus. However, Wnt1(Cre2SOR) mutants had an open cranial neural tube phenotype that was not evident in Wnt1(Cre) mutants. In O9-1 CNC cells, the loss of Yap impaired smooth muscle cell differentiation. RNA-sequencing data indicated that Yap and Taz regulate genes encoding Fox transcription factors, specifically Foxc1. Proliferation was reduced in the branchial arch mesenchyme of Yap and Taz CNC conditional knockout (CKO) embryos. Moreover, Yap and Taz CKO embryos had cerebellar aplasia similar to Dandy-Walker spectrum malformations observed in human patients and mouse embryos with mutations in Foxc1. In embryos and O9-1 cells deficient for Yap and Taz, Foxc1 expression was significantly reduced. Analysis of Foxc1 regulatory regions revealed a conserved recognition element for the Yap and Taz DNA binding co-factor Tead. ChIP-PCR experiments supported the conclusion that Foxc1 is directly regulated by the Yap-Tead complex. Our findings uncover important roles for Yap and Taz in CNC diversification and development.
河马信号通路在颅神经嵴（CNC）发育中的作用尚不清楚。我们使用Wnt1（Cre）和Wnt1（Cre2SOR）驱动因子有条件地敲除小鼠CNC中的Yap和Taz。当使用任一Cre驱动因子时，CNC中Yap和Taz的缺失会导致鳃弓血管肿大、出血以及脑积水。然而，Wnt1（Cre2SOR）突变体具有开放的颅神经管表型，这在Wnt1（Cre）突变体中并不明显。在O9-1 CNC细胞中，Yap的缺失损害了平滑肌细胞的分化。RNA测序数据表明，Yap和Taz调节编码Fox转录因子的基因，特别是Foxc1。Yap和Taz CNC条件性敲除（CKO）胚胎的鳃弓间充质增殖减少。此外，Yap和Taz CKO胚胎具有小脑发育不全，类似于在人类患者和Foxc1突变的小鼠胚胎中观察到的Dandy-Walker谱系畸形。在Yap和Taz缺陷的胚胎和O9-1细胞中，Foxc1表达显著降低。对Foxc1调控区域的分析揭示了Yap和Taz DNA结合辅助因子Tead的保守识别元件。染色质免疫沉淀-聚合酶链反应（ChIP-PCR）实验支持了Foxc1由Yap-Tead复合物直接调控的结论。我们的研究结果揭示了Yap和Taz在CNC多样化和发育中的重要作用。
