Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan.
Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan.
Biochim Biophys Acta Mol Cell Res. 2017 Mar;1864(3):463-474. doi: 10.1016/j.bbamcr.2016.12.013. Epub 2016 Dec 13.
Neural crest cells are multipotent progenitors that migrate extensively and differentiate into numerous derivatives. The developmental plasticity and migratory ability of neural crest cells render them an attractive model for studying numerous aspects of cell progression. We observed that zebrafish rgs2 was expressed in neural crest cells. Disrupting Rgs2 expression by using a dominant negative rgs2 construct or rgs2 morpholinos reduced GTPase-activating protein activity, induced the formation of neural crest progenitors, increased the proliferation of nonectomesenchymal neural crest cells, and inhibited the formation of ectomesenchymal neural crest derivatives. The transcription of pparda (which encodes Pparδ, a Wnt-activated transcription factor) was upregulated in Rgs2-deficient embryos, and Pparδ inhibition using a selective antagonist in the Rgs2-deficient embryos repaired neural crest defects. Our results clarify the mechanism through which the Rgs2-Pparδ cascade regulates neural crest development; specifically, Pparδ directly binds to the promoter and upregulates the transcription of the neural crest specifier sox10. This study reveals a unique regulatory mechanism, the Rgs2-Pparδ-Sox10 signaling cascade, and defines a key molecular regulator, Rgs2, in neural crest development.
神经嵴细胞是多能祖细胞，广泛迁移并分化为众多衍生物。神经嵴细胞的发育可塑性和迁移能力使其成为研究细胞进展众多方面的理想模型。我们观察到斑马鱼 rgs2 在神经嵴细胞中表达。使用显性负 rgs2 构建体或 rgs2 嵌合寡核苷酸破坏 Rgs2 表达会降低 GTPase 激活蛋白的活性，诱导神经嵴祖细胞的形成，增加非外胚层神经嵴细胞的增殖，并抑制外胚层神经嵴衍生物的形成。在 Rgs2 缺陷胚胎中，pparda（编码 Wnt 激活转录因子 Pparδ）的转录上调，并且在 Rgs2 缺陷胚胎中使用选择性拮抗剂抑制 Pparδ 修复了神经嵴缺陷。我们的结果阐明了 Rgs2-Pparδ 级联调节神经嵴发育的机制；具体而言，Pparδ 直接结合启动子并上调神经嵴特异性转录因子 sox10 的转录。这项研究揭示了一种独特的调节机制，即 Rgs2-Pparδ-Sox10 信号级联，并定义了神经嵴发育中的关键分子调节剂 Rgs2。
