RESUMO
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.
Assuntos
Diferenciação Celular/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Neuregulina-1/metabolismo , Neurônios/fisiologia , Isoformas de Proteínas/metabolismo , Células-Tronco/fisiologia , Fatores de Transcrição/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Neuregulina-1/genética , Neurônios/citologia , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-4 , Células-Tronco/citologia , Fatores de Transcrição/genéticaRESUMO
The history of sciences is characterized by major discoveries, but also by challenges of theories or dogma previously established and accepted by everybody. One of the recent examples illustrating such a questioning relates to the demonstration of the persistence of a cerebral neurogenesis in the adult brain, including in human. This adult neurogenesis is however limited, both in space (it concerns only the subventricular zone and the gyrus dentatus in the hippocampus) and the type of newly-formed neurons (interneurones which most of them are GABAergic and present respectively in the olfactive bulb and CA1 area of the hippocampus). Moreover, this neurogenesis does not seem to be recruited after a brain lesion, a situation which explains why functional recovery when it is observed remains a consequence of brain plasticity. We thus legitimately address the question about the physiological role of this adult brain neurogenesis as well as a possible implication in the aetiology of various neurological disorders, like the neurodegenerative diseases or epilepsy, but also in psychiatric diseases like depression.
