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Role of huntingtin during cortical development

Objectifs

The objective of the proposed training period is to decipher the role of huntingtin (HTT), the protein mutated in Huntington disease, during cortical development focusing on axogenesis.

Résumé

Most of the interest in the HTT protein has centered on the fact that, when mutated, HTT causes Huntington’s disease (HD), a devastating neurological disorder. Since HD is characterized by an adult onset, the dysfunction and death of adult neurons, studies have focused on the toxic effects elicited by mutant HTT in adultpost-mitotic neurons. However, the protein is ubiquitous and expressed in the developing embryo where it plays an essential role as revealed by the early embryonic lethality at day 7.5 of the HTT knock-out mice. Anyway, the roles of the wild-type and mutant protein during development have been understudied. We previously found that HTT is key for cortical neurogenesis through the regulation of: (i) division of progenitor cells division and (ii) of migration and maturation of post-mitotic neurons migration and maturation. These mechanisms are dysregulated in HD conditions leading to abnormal cortical development. We now propose to study the role of HTT in axonal growth and the establishment of axonal connections during cortical development.

Méthodes

Cell biology (cell cultures; immunocytochemistry), immunoblotting, histology (immunohistochemistry), imaging.

Références

  • Molina-Calavita M, Barnat M, Elias S, Aparicio E, Piel M and Humbert S (2014). Mutant huntingtin affects cortical progenitor cell division and development of the mouse neocortex. J Neurosci, 34, 10034-10040.
  • Elias S, McGuire JR, Yu H and Humbert S (2015). Huntingtin is required for epithelial polarity through RAB11A mediated apical trafficking of PAR3-aPKC. Plos Biol, 13:e1002142.
  • Barnat M, Le Friec J, Benstaali C and Humbert S (2017). Huntingtin-mediated Multipolar-Bipolar Transition of Newborn Cortical Neurons is Critical for their Postnatal Neuronal Morphology. Neuron, 93, 99-114.

Domaines d'expertise requis

Molecular and cellular neurobiology, brain development (cortex), neuroscience.

Contacts

Sandrine Humbert, DR Inserm
Email : sandrine.humbert@inserm.fr
Tél: 04 56 52 05 63

Mise à jour le 6 juin 2019

Contacts

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