Institute of Physiology, Department of Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3546-51. doi: 10.1073/pnas.1108718109. Epub 2012 Feb 14.
First insights into the molecular programs orchestrating the progression from neural stem cells to cortical projection neurons are emerging. Loss of the transcriptional regulator Ski has been linked to the human 1p36 deletion syndrome, which includes central nervous system defects. Here, we report critical roles for Ski in the maintenance of the neural stem cell pool and the specification of callosal neurons. Ski-deficient callosal neurons lose their identity and ectopically express the transcription factor Ctip2. The misspecified callosal neurons largely fail to form the corpus callosum and instead redirect their axons toward subcortical targets. We identify the chromatin-remodeling factor Satb2 as a partner of Ski, and show that both proteins are required for transcriptional repression of Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski to the Ctip2 locus, and Ski attracts histone deacetylases, thereby enabling the formation of a functional nucleosome remodeling and deacetylase repressor complex. Our findings establish a central role for Ski-Satb2 interactions in regulating transcriptional mechanisms of callosal neuron specification.
目前，人们对于调控神经干细胞向皮质投射神经元发育进程的分子程序已经有了初步的认识。转录调控因子 Ski 的缺失与人类 1p36 缺失综合征有关，该综合征包括中枢神经系统缺陷。在这里，我们报告了 Ski 在维持神经干细胞池和皮层神经元特化过程中的关键作用。Ski 缺失的皮层神经元会失去其特性，并异位表达转录因子 Ctip2。这些特化错误的皮层神经元大部分未能形成胼胝体，而是将其轴突转向皮质下靶标。我们鉴定了染色质重塑因子 Satb2 是 Ski 的一个伴侣蛋白，并表明这两种蛋白都需要在皮层神经元中抑制 Ctip2 的转录。我们提出了一个模型，其中 Satb2 将 Ski 招募到 Ctip2 基因座，而 Ski 则吸引组蛋白去乙酰化酶，从而形成功能性核小体重塑和去乙酰化酶抑制剂复合物。我们的研究结果确立了 Ski-Satb2 相互作用在调节皮层神经元特化的转录机制中的核心作用。
