Wang Hui, Wang Chengdong, Long Qi, Zhang Yuan, Wang Meiling, Liu Jie, Qi Xufeng, Cai Dongqing, Lu Gang, Sun Jianmin, Yao Yong-Gang, Chan Wood Yee, Chan Wai Yee, Deng Yi, Zhao Hui
Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Development. 2021 May 15;148(10). doi: 10.1242/dev.199441. Epub 2021 May 17.
The focal adhesion protein Kindlin2 is essential for integrin activation, a process that is fundamental to cell-extracellular matrix adhesion. Kindlin 2 (Fermt2) is widely expressed in mouse embryos, and its absence causes lethality at the peri-implantation stage due to the failure to trigger integrin activation. The function of kindlin2 during embryogenesis has not yet been fully elucidated as a result of this early embryonic lethality. Here, we showed that kindlin2 is essential for neural crest (NC) formation in Xenopus embryos. Loss-of-function assays performed with kindlin2-specific morpholino antisense oligos (MOs) or with CRISPR/Cas9 techniques in Xenopus embryos severely inhibit the specification of the NC. Moreover, integrin-binding-deficient mutants of Kindlin2 rescued the phenotype caused by loss of kindlin2, suggesting that the function of kindlin2 during NC specification is independent of integrins. Mechanistically, we found that Kindlin2 regulates the fibroblast growth factor (FGF) pathway, and promotes the stability of FGF receptor 1. Our study reveals a novel function of Kindlin2 in regulating the FGF signaling pathway and provides mechanistic insights into the function of Kindlin2 during NC specification.
粘着斑蛋白Kindlin2对于整合素激活至关重要，而整合素激活是细胞与细胞外基质粘附的基础过程。Kindlin 2（Fermt2）在小鼠胚胎中广泛表达，由于无法触发整合素激活，其缺失会导致着床期致死。由于这种早期胚胎致死性，Kindlin2在胚胎发生过程中的功能尚未完全阐明。在此，我们表明Kindlin2对于非洲爪蟾胚胎中的神经嵴（NC）形成至关重要。在非洲爪蟾胚胎中使用Kindlin2特异性吗啉代反义寡核苷酸（MOs）或CRISPR/Cas9技术进行的功能丧失实验严重抑制了NC的特化。此外，Kindlin2的整合素结合缺陷型突变体挽救了因Kindlin2缺失导致的表型，这表明Kindlin2在NC特化过程中的功能独立于整合素。从机制上讲，我们发现Kindlin2调节成纤维细胞生长因子（FGF）途径，并促进FGF受体1的稳定性。我们的研究揭示了Kindlin2在调节FGF信号通路中的新功能，并为Kindlin2在NC特化过程中的功能提供了机制性见解。
