Etude des isoformes de Neurégulines-1 et -2 dans la prolifération et la différenciation des cellules souches nerveuses au cours du développement

Au cours de ce travail, nous avons cherché de préciser le rôle de cette famille de facteur de croissance dans le choix d’un destin cellulaire au cours du développement, tout en gardant à l’esprit leur éventuel potentiel dans le cadre d’une thérapie cellulaire chez l’adulte. Nous avons donc tenté de répondre aux questions suivantes : 1) est-il possible d’influencer le choix d’un destin cellulaire particulier dans les cellules souches nerveuses sous l’effet des Neurégulines ; 2) si oui, quel(s) serait (seraient) le(s) mécanisme(s) moléculaire(s) éventuellement recrutable ou applicable en terme de régénération. Le chapitre II est consacré à l’étude des Neurégulines-1 et leurs effets sur la prolifération et la différenciation des cellules souches nerveuses in vitro. Dans ce chapitre, nous décrivons un mécanisme moléculaire original responsable de la modulation de la différenciation par les Neurégulines-1 et qui établit un line direct entre les influences intrinsèques et extrinsèques telles que nous les avons rappelées en préambule du point 2 de cette introduction (Edlund and Jessell, 1999). La plupart des résultats de ce chapitre font l’objet d’un article actuellement sous presse (appendice 2). Dans le chapitre III, nous décrivons les résultats préliminaires obtenus dans l’étude du rôle du rôle de Nrg-2 dans ces mécanismes. C’est sur la base de la similitude structurelle et topologique des isoformes codées par les deux gènes que nous avons entrepris cette dernière partie de notre travail

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

Inactivation of genes coding for mitochondrial Nd7 and Nd9 complex I subunits in Chlamydomonas reinhardtii. Impact of complex I loss on respiration and energetic metabolism.

In Chlamydomonas, unlike in flowering plants, genes coding for Nd7 (NAD7/49kDa) and Nd9 (NAD9/30kDa) core subunits of mitochondrial respiratory-chain complex I are nucleus-encoded. Both genes possess all the features that facilitate their expression and proper import of the polypeptides in mitochondria. By inactivating their expression by RNA interference or insertional mutagenesis, we show that both subunits are required for complex I assembly and activity. Inactivation of complex I impairs the cell growth rate, reduces the respiratory rate, leads to lower intracellular ROS production and lower expression of ROS scavenging enzymes, and is associated to a diminished capacity to concentrate CO2 without compromising photosynthetic capacity.Peer reviewe

Inactivation of genes coding for mitochondrial Nd7 and Nd9 complex I subunits in Chlamydomonas reinhardtii. Impact of complex I loss on respiration and energetic metabolism.

In Chlamydomonas, unlike in flowering plants, genes coding for Nd7 (NAD7/49kDa) and Nd9 (NAD9/30kDa) core subunits of mitochondrial respiratory-chain complex I are nucleus-encoded. Both genes possess all the features that facilitate their expression and proper import of the polypeptides in mitochondria. By inactivating their expression by RNA interference or insertional mutagenesis, we show that both subunits are required for complex I assembly and activity. Inactivation of complex I impairs the cell growth rate, reduces the respiratory rate, leads to lower intracellular ROS production and lower expression of ROS scavenging enzymes, and is associated to a diminished capacity to concentrate CO2 without compromising photosynthetic capacity.Peer reviewe

Adult neurogenesis or the falling of a dogma

peer reviewedThe 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