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

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.