Kinetic Analysis of npBAF to nBAF Switching Reveals Exchange of SS18 with CREST and Integration with Neural Developmental Pathways
Kinetic Analysis of npBAF to nBAF Switching Reveals Exchange of SS18 with CREST and Integration with Neural Developmental Pathways
复制标题
DOI：
10.1523/jneurosci.1258-13.2013
复制
发表时间：
2013-06-19
影响因子：
5.3
通讯作者：
Crabtree, Gerald R.
中科院分区：
文献类型：
--
作者：
Staahl, Brett T.;Tang, Jiong;Crabtree, Gerald R.
在脊椎动物神经系统的发育过程中，神经祖细胞分裂，产生退出有丝分裂的后代，然后迁移到它们精心制作特定形态和突触连接的位点。神经元中的有丝分裂退出伴随着ATP依赖性染色质调节复合物从神经祖细胞Brg/Brm相关因子（npBAF）到神经元特异性nBAF复合物的基本转换，其部分由miR-9/9* 和miR-124驱动。在成纤维细胞中重现这种microRNA/染色质开关导致它们直接转化为神经元。我们已经定义了动力学的神经元特异性BAF复合物组装在诱导神经元的形成从小鼠胚胎干细胞，人成纤维细胞，和正常的小鼠神经分化，并使用蛋白质组学分析，发现这种开关还包括删除SS 18和它的替代CREST在有丝分裂出口。我们发现染色质重塑机制的转换与神经源性转录因子的广泛转换高度相关。神经干细胞中SS 18的敲低导致细胞周期退出和自我更新失败，而神经元中SS 18的持续表达阻断树突状生长，强调了亚基转换的重要性。由于BAF亚基的显性突变是不同神经元类型中产生的广泛不同的人类神经系统疾病的基础，我们的研究表明，这些疾病的特征必须在神经元中不同的BAF组装体的背景下进行解释，而不是单一的哺乳动物SWItch/蔗糖非发酵（mSWI/SNF）复合物。
During the development of the vertebrate nervous system, neural progenitors divide, generate progeny that exit mitosis, and then migrate to sites where they elaborate specific morphologies and synaptic connections. Mitotic exit in neurons is accompanied by an essential switch in ATP-dependent chromatin regulatory complexes from the neural progenitor Brg/Brm-associated factor (npBAF) to neuron-specific nBAF complexes that is in part driven by miR-9/9* and miR-124. Recapitulating this microRNA/chromatin switch in fibroblasts leads to their direct conversion to neurons. We have defined the kinetics of neuron-specific BAF complex assembly in the formation of induced neurons from mouse embryonic stem cells, human fibroblasts, and normal mouse neural differentiation and, using proteomic analysis, found that this switch also includes the removal of SS18 and its replacement by CREST at mitotic exit. We found that switching of chromatin remodeling mechanisms is highly correlated with a broad switch in the use of neurogenic transcription factors. Knock-down of SS18 in neural stem cells causes cell-cycle exit and failure to self-renew, whereas continued expression of SS18 in neurons blocks dendritic outgrowth, underlining the importance of subunit switching. Because dominant mutations in BAF subunits underlie widely different human neurologic diseases arising in different neuronal types, our studies suggest that the characteristics of these diseases must be interpreted in the context of the different BAF assemblies in neurons rather than a singular mammalian SWItch/sucrose nonfermentable (mSWI/SNF) complex.