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Etude du rôle de la voie NOTCH dans la régulation de Shh au cours du développement du cerveau antérieur chez les vertébrés

Abstract : Holoprosencephaly (HPE) is a developmental pathology defined by a lack of forebrain cleavage along the midline and characterized by phenotypic heterogeneity and incomplete penetrance. The morphogen SHH is the main molecule involved in the onset of HPE. The NOTCH pathway has also been implicated in the occurrence of HPE in patients. In this study, I showed that NOTCH pathway activation was necessary to maintain Shh expression in the ventral forebrain. Furthermore, I demonstrated the implication of NOTCH pathway in early neurogenesis in the hypothalamus. Finally, a hypomorphic mouse model for both SHH and NOTCH pathways has shown the appearance of pituitary gland dysplasia associated with basisphenoid bone malformations reminiscent of abnormalities observed in HPE patients. This work has allowed us to generate an animal model reproducing an HPE phenotype based on the partial inactivation of two molecular signaling pathways. This result reinforces the hypothesis of a multigenic transmission for this complexe pathology that affects midline development.
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Submitted on : Wednesday, September 9, 2020 - 2:54:41 PM
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Houda Hamdi-Rozé. Etude du rôle de la voie NOTCH dans la régulation de Shh au cours du développement du cerveau antérieur chez les vertébrés. Biologie cellulaire. Université Rennes 1, 2019. Français. ⟨NNT : 2019REN1B046⟩. ⟨tel-02934607⟩

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