Hu Na, Strobl-Mazzulla Pablo H, Simoes-Costa Marcos, Sánchez-Vásquez Estefania, Bronner Marianne E
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125 and.
Laboratorio de biología del desarrollo, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, 7130 Buenos Aires, Argentina.
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17911-6. doi: 10.1073/pnas.1318408111. Epub 2014 Dec 1.
Neural crest stem cells arise within the central nervous system but then undergo an epithelial-to-mesenchymal transition to migrate away and contribute to the peripheral nervous system and craniofacial skeleton. Here we show that DNA methyltransferase 3B (DNMT3B) is responsible for the loss of competence of dorsal neural tube cells to generate emigrating neural crest cells. DNMT3B knockdown results in up-regulation of neural crest markers, prolonged neural crest emigration, and subsequent precocious neuronal differentiation of the trigeminal ganglion. We find that DNMT3B binds to the promoter of Sox10, known to be important for neural crest emigration and lineage acquisition. Bisulfite sequencing further reveals methylation of the Sox10 promoter region upon cessation of emigration in normal embryos, whereas this mark is reduced after DNMT3B loss. Taken together, these results reveal the importance of DNA methylation in regulating the ability of neural tube cells to produce neural crest cells and the timing of peripheral neuron differentiation.
神经嵴干细胞产生于中枢神经系统内，但随后经历上皮-间充质转化以迁移离开，并对外周神经系统和颅面骨骼做出贡献。在此我们表明，DNA甲基转移酶3B（DNMT3B）负责背侧神经管细胞产生迁移神经嵴细胞能力的丧失。DNMT3B基因敲低导致神经嵴标志物上调、神经嵴迁移延长以及随后三叉神经节神经元的早熟分化。我们发现DNMT3B与Sox10的启动子结合，已知Sox10对神经嵴迁移和谱系获得很重要。亚硫酸氢盐测序进一步揭示，在正常胚胎中迁移停止时Sox10启动子区域发生甲基化，而在DNMT3B缺失后这种标记减少。综上所述，这些结果揭示了DNA甲基化在调节神经管细胞产生神经嵴细胞的能力以及外周神经元分化时机方面的重要性。
