Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America.
PLoS Biol. 2018 Jun 27;16(6):e2004425. doi: 10.1371/journal.pbio.2004425. eCollection 2018 Jun.
The neural crest is induced at the neural plate border during gastrulation by combined bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling. While intermediate BMP levels are critical for this induction, secreted BMP inhibitors are largely absent from the neural plate border. Here, we propose a morphogen model in which intracellular attenuation of BMP signaling sets the required intermediate levels to maintain neural crest induction. We show that the scaffold protein casein kinase interacting protein 1 (CKIP-1) and ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) are coexpressed with BMP4 at the chick neural plate border. Knockdown of CKIP-1 during a critical period between gastrulation and neurulation causes neural crest loss. Consistent with specific BMP modulation, CKIP-1 loss suppresses phospho-Smads 1/5/8 (pSmad1/5/8) and BMP reporter output but has no effect on Wnt signaling; Smurf1 overexpression (OE) acts similarly. Epistasis experiments further show that CKIP-1 rescues Smurf1-mediated neural crest loss. The results support a model in which CKIP-1 suppresses Smurf1-mediated degradation of Smads, uncovering an intracellular mechanism for attenuation of BMP signaling to the intermediate levels required for maintenance of neural crest induction.
神经嵴在原肠胚形成过程中，由骨形态发生蛋白（BMP）、成纤维细胞生长因子（FGF）和 Wnt 信号的联合作用，在神经板边缘被诱导产生。虽然中间水平的 BMP 对这种诱导至关重要，但分泌的 BMP 抑制剂在神经板边缘基本不存在。在这里，我们提出了一个形态发生模型，其中 BMP 信号的细胞内衰减设定了维持神经嵴诱导所需的中间水平。我们表明，支架蛋白酪蛋白激酶相互作用蛋白 1（CKIP-1）和泛素连接酶 Smad 泛素调节因子 1（Smurf1）与 BMP4 在鸡神经板边缘共同表达。在原肠胚形成和神经胚形成之间的关键时期，CKIP-1 的敲低会导致神经嵴丧失。与特定的 BMP 调节一致，CKIP-1 的缺失抑制了磷酸化 Smad1/5/8（pSmad1/5/8）和 BMP 报告基因产物，但对 Wnt 信号没有影响；Smurf1 的过表达（OE）也有类似的作用。上位性实验进一步表明，CKIP-1 可以挽救 Smurf1 介导的神经嵴丢失。结果支持了这样一种模型，即 CKIP-1 抑制了 Smurf1 介导的 Smads 降解，揭示了一种细胞内机制，用于衰减 BMP 信号，使其达到维持神经嵴诱导所需的中间水平。
