Liu Bin, Ma Anyun, Zhang Feng, Wang Yumeng, Li Zengmin, Li Qingyu, Xu Zhiheng, Zheng Yufang
State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University.
The Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China, 200433.
Sci Rep. 2016 Feb 12;6:21534. doi: 10.1038/srep21534.
Neurons and glia cells are differentiated from neural stem/progenitor cells (NSCs/NPCs) during brain development. Concomitant activation of JAK/STAT and NOTCH1 signaling is required for gliogenesis, a process to generate glia cells to ensure proper brain functions. NOTCH1 signaling is down-regulated during neurogenesis and up-regulated during gliogenesis. However, the underlying mechanism remains elusive. We report here that cardiotrophin-1 (CT-1) activates NOTCH1 signaling through the up-regulation of ADAM10, a rate-limiting factor of NOTCH1 signaling activation. We found that a transcriptional factor, Myc-associated zinc finger protein (MAZ), plays an important role in ADAM10 transcription in response to CT-1 in NPCs. MAZ knockdown inhibits CT-1 stimulated gliogenesis and it can be rescued by over-expressing human NICD. Our results provide a link between NOTCH1 activation and neuronal secreted CT-1, suggesting that CT-1 plays an important role in ensuring the coordinated activation of NOTCH1 signaling during gliogenesis.
在大脑发育过程中，神经元和神经胶质细胞由神经干/祖细胞（NSCs/NPCs）分化而来。神经胶质生成（即生成神经胶质细胞以确保大脑正常功能的过程）需要JAK/STAT和NOTCH1信号的协同激活。NOTCH1信号在神经发生过程中被下调，而在神经胶质生成过程中被上调。然而，其潜在机制仍不清楚。我们在此报告，心肌营养素-1（CT-1）通过上调ADAM10（NOTCH1信号激活的限速因子）来激活NOTCH1信号。我们发现，一种转录因子，即Myc相关锌指蛋白（MAZ），在NPCs中响应CT-1时对ADAM10转录起重要作用。MAZ敲低抑制CT-1刺激的神经胶质生成，而过表达人NICD可使其恢复。我们的结果揭示了NOTCH1激活与神经元分泌的CT-1之间的联系，表明CT-1在确保神经胶质生成过程中NOTCH1信号的协同激活方面发挥重要作用。
