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Rôle du récepteur nucléaire RORα dans la survie et la différenciation

Abstract : RORα is a transcription factor belonging to the nuclear receptor superfamily. RORα disruption in homozygous staggerer mutants leads to a variety of age-related phenotypes, including neurodegeneration, immunodeficiencies, muscular atrophy, osteoporosis and atherosclerosis (for review, see ). Most obviously, staggerer mutants display a strong ataxic phenotype, associated with severe cerebellar degeneration. Most cerebellar Purkinje cells (PCs) (82%) undergo cell death during postnatal development, whilst those remaining PCs display an immature shape. However, whether this immature shape is due to the absence of RORα or to secondary events consecutive to PC death was unknown.
During a first part of my thesis, I studied the implication of RORα in the neuronal survival in RORα overexpressing experiments. I have constructed a lentiviral vector to perform efficient RORα overexpression in both cortical and cerebellar cultures. By FACS quantification, the survival rate of RORα-overexpressing cortical neurons was evaluated in response to different stressors disturbing redox homeostasis, such as Aβ peptide, c2 ceramide and H2O2. We have shown that hRORα1 overexpression provides neuroprotection against reactive oxygen species (ROS)-induced apoptosis and real-time RT-PCR revealed an overexpression of the anti-oxidant enzymes glutathione peroxidase 1 and peroxiredoxin 6. Down-regulation of these enzymes by si-RNA experiments partially suppressed the RORα-mediated neuroprotection, further demonstrating their implication in the protection provided by RORα . RORα appears thus as a factor controlling the oxidative stress in neurons. To test whether an overexpression of RORα could protect Purkinje cells from death during development, we studied the survival of RORα-overexpressing PCs in a model which reproduces a developmental cell-death in organotypic cultures. Quantification of the PC number showed an increased survival of lentiviral-mediated RORα-overexpressing PCs, suggesting that the age-dependant apoptotic cell death in culture is decreased when RORα is overexpressed, indicating a neuroprotective role of RORα against developmental cell death. We are currently investigating the ROS pathway in the RORα-overexpressing PCs .
In a second part of my thesis, I studied the role of RORα in the PC differentiation process in organotypic culture. As observed in vivo, in these cultures fusiform PCs with embryonic bipolar shape undergo regression prior to the outgrowth of the ultimate dendritic tree. We show that lentiviral-mediated overexpression of RORα in fusiform PCs leads to a cell-autonomous accelerated progression of dendritic differentiation. In addition, we demonstrate that RORα is necessary for the regressive events of early differentiation: while staggerer RORα-deficient PCs remain in the embryonic fusiform stage, replacement of RORα restores normal dendritogenesis. In this study, we have thus demonstrated that RORα controls initial dendritic remodelling during development, particularly the first phase of dendritic regression of the fusiform PCs .
In a third part of my thesis, I studied the implication of RORα in the thyroid hormone (TH) signalling during early PC dendritic differentiation. We show that TH treatment leads to an upregulation of RORα expression in PCs. Moreover, action of TH requires RORα expression, since we show that, unlike controls, TH has no effect on the PC differentiation in RORα-deficient PCs. Our results strongly suggest that TH action on the early PC dendritic is mediated by RORα . We are now exploring whether RORα is a target gene of thyroid nuclear receptor in PCs.
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Submitted on : Wednesday, July 12, 2006 - 10:01:05 AM
Last modification on : Sunday, June 26, 2022 - 9:48:57 AM
Long-term archiving on: : Monday, September 20, 2010 - 4:28:50 PM


  • HAL Id : tel-00080417, version 2


Fatiha Boukhtouche. Rôle du récepteur nucléaire RORα dans la survie et la différenciation
neuronale. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2006. Français. ⟨NNT : ⟩. ⟨tel-00080417v2⟩



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