神经调节素 1 通过与 Swi/Snf 复合物相互作用调节神经干细胞的体外分化。

Neuregulin-1 modulates the differentiation of neural stem cells in vitro through an interaction with the Swi/Snf complex.

机构信息

Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Belgium.

出版信息

Mol Cell Neurosci. 2010 Jan;43(1):72-80. doi: 10.1016/j.mcn.2009.09.003. Epub 2009 Sep 23.

DOI:10.1016/j.mcn.2009.09.003

PMID:19781646

Abstract

The neuregulin-1 (Nrg-1) gene is translated into several protein isoforms, which are either secreted or membrane-anchored. In vitro, neural stem cells (NSC) express mainly the cystein-rich-domain NRG (CRD-NRG) isoform, a membrane-anchored type III form. This isoform exhibits a cystein-rich-domain, which constitutes a second transmembrane domain and can be cleaved to release both a signaling EGF-containing domain (ECD) at the cell surface and an intracellular domain (ICD). The main goal of this paper was to determine the exact role of ECD and ICD in NSC survival and differentiation. Using an siRNA approach, we demonstrated that CRD-NRG inhibition was followed by a decrease in NSC proliferation and of neuronal or oligodendroglial differentiation. Overexpression of ICD but not ECD was followed by a decrease in NSC proliferation and an increase in neuronal and oligodendroglial differentiation. Moreover, we showed that ICD physically interacted in cultured NSC with BRM and BAF57, two members of the Swi/Snf remodeling complex, and that ICD stimulation of neuronal cell differentiation is dependent on the presence of BAF57.

摘要

神经调节蛋白 1（Nrg-1）基因被翻译成几种蛋白质同工型，这些同工型要么分泌，要么锚定在细胞膜上。在体外，神经干细胞（NSC）主要表达富含半胱氨酸的结构域 Nrg（CRD-Nrg）同工型，这是一种膜锚定的 III 型形式。这种同工型具有富含半胱氨酸的结构域，构成第二个跨膜结构域，可被切割，从而在细胞表面释放具有信号 EGF 结构域（ECD）的信号肽和细胞内结构域（ICD）。本文的主要目的是确定 ECD 和 ICD 在 NSC 存活和分化中的确切作用。通过 siRNA 方法，我们证明了 CRD-Nrg 抑制后 NSC 增殖减少，神经元或少突胶质分化减少。ICD 的过表达而不是 ECD 的过表达导致 NSC 增殖减少，神经元和少突胶质分化增加。此外，我们表明 ICD 在培养的 NSC 中与 BRM 和 BAF57 相互作用，BRM 和 BAF57 是 Swi/Snf 重塑复合物的两个成员，而 ICD 刺激神经元细胞分化依赖于 BAF57 的存在。