Rôles tardifs du facteur de transcription HNF-6 dans le développement des jonctions neuromusculaires et du cervelet
(2013)
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- Authors
- Supervisors
- Clotman, Frédéric
- Abstract
- (en) In humans, a large number of diseases and lesions of the CNS, leading to abnormalities of locomotion have been described. Locomotor activity is regulated at three levels in the CNS. Motor areas receive information that will be transmitted to the spinal cord via the pyramidal or extrapyramidal tracts, resulting in an appropriate motor response by effector muscles. In addition, the cerebellum and basal ganglia are involved in the coordination, planning and execution of motor programs. It is important to understand the cells, structures and circuits involved in locomotion in order to better understand the mechanisms of these lesions and diseases and to apply them in humans. The family of the Onecut transcription factors comprises three members in mammals, namely HNF-6, OC-2 and OC-3. They play important roles in the CNS including cell differentiation, maintenance of cell identity and cell migration. Hnf6-/- mice display a paralysis of the hindlimbs at birth. The goal of my thesis was to understand the origin of the paralysis in these mice. To assess locomotor defects in adult Hnf6-/- mice, we performed behavioral tests. These mice display a reduction of muscular strength and an abnormal positioning of the hindlimbs, and a defect in the coordination and in the balance. These defects suggest that the neuromuscular junction and the cerebellum are altered in Hnf6-/- mice. Therefore, we aimed at identifying abnormalities of the neuromuscular junctions and of the cerebellum in mice Hnf6-/- and to characterize the roles of HNF-6 in these two structures. The morphology of the neuromuscular junctions and the localization of synaptophysin were abnormal in Hnf6-/- mice. HNF-6 regulates, directly or indirectly, the expression of agrin and neuregulin, two genes necessary for proper formation and maintenance of the neuromuscular junction. In addition, the organization of Purkinje cells in the cerebellum was abnormal and characterized by a superposition of cells, a localization of cells in the granular layer or the absence of cells, depending on the location. These results show that HNF-6 is required for the organization of Purkinje cells. To conclude, we identified two new roles of HNF-6 during this work, namely in the formation of the NMJ and in the organization of Purkinje cells.
- Affiliations
Citations
Audouard, E. (2013). Rôles tardifs du facteur de transcription HNF-6 dans le développement des jonctions neuromusculaires et du cervelet. https://hdl.handle.net/2078.5/206813