Team "Neural progenitors and brain pathologies"

Director : Sandrine HUMBERT

Development of the cerebral cortex and adult hippocampal neurogenesis are complex processes where huntingtin, the protein mutated in Huntington disease, plays a central role. Understanding these mechanisms will open new avenues potentially leading to treatment of Huntington disease and other neuropathologies.

Keywords

Huntingtin, Huntington Disease, cortical development, adult hippocampal neurogenesis, division, polarity, differentiation, scaffold protein.

Themes of research

Our overall goal is to understand the mechanisms coordinating division, cell fate choices and differentiation of neuronal stem/progenitor cells during development and adulthood. We are tackling these issues through the study of one protein, huntingtin. Huntingtin is the perfect model protein, being a scaffold for complexes involved in spindle orientation, cell-cell junctions and cell polarization. Furthermore, huntingtin is mutated in Huntington disease, an inherited neurodegenerative disorder with adult onset. Studying huntingtin thus allows integration of cellular mechanisms and physiological and pathophysiological conditions.

More specifically, we are studying the contribution of huntingtin to different steps of cortical development and adult hippocampal neurogenesis. We aim to define the molecular complexes involved. We also address the questions of how these mechanisms participate in the proper establishment and maintenance of neuronal networks and whether these pathways are altered in Huntington disease. Our working hypothesis is that abnormal development could be a predisposing factor contributing to the symptoms observed in Huntington disease. In the adult, we propose that the depressive behaviour observed in patients is not just an epiphenomenon to a severe disorder with a fatal outcome, but the result of a modification in the biological function of huntingtin in adult neurogenesis.

Techniques used :

  • Molecular biology and biochemistry

  • Electrophysiology

  • Cell biology: primary cultures of neurons and neural stem cells, subcellular localization of proteins, analysis of cellular and intracellular dynamics

  • Microscopy: confocal, spinning disc and light sheet microscopy, live imaging (living cells, organotypic slices)

  • Mouse models: genetic models, in utero electroporation, histology, phenotypic analysis

Partners :  


Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, Kassem R, Lenoir S, Agasse F, Braz B, Liu JP, Ighil J, Tessier A, Zeitlin SO, Duyckaerts C, Dommergues M, Durr A, Humbert S (2020). Huntington disease alters human neurodevelopment. Science, 369, 787-793.

Agasse F, Mendez-David I, Christaller W, Carpentier R, Braz B, David DJ, Saudou F, Humbert S (2020). Chronic corticosterone elevation suppresses adult hippocampal neurogenesis by hyperphorphorylating Huntingtin. Cell Reports, 32, 107865.

Coarelli G, Diallo A, Thion MS, Rinaldi D, Calvas F, Boukbiza OL, Tataru A, Charles P, Tranchant C, Marelli C, Ewenczyk C, Tchikviladzé M, Monin ML, Carlander B, Anheim M, Brice A, Mochel F, Tezenas du Montcel S, Humbert S*, Durr A* (2017). Low cancer prevalence in polyglutamine expansion diseases. Neurology, 88, 1114-1119. *co-corresponding authors.

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.
 

Thion MS, McGuire JR, Sousa CM, Fuhrmann L, Fitamant J, Leboucher S, Vacher S, Tezenas du Montcel S, Bièche I, Bernet A, Patrick Mehlen P, Anne Vincent-Salomon A, and Humbert, S (2015). Unravelling the role of huntingtin in breast cancer metastasis. J. Natl. Cancer Inst., doi: 10.1093/jnci/djv208.
 

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.
 

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, Thion MS, Yu H, Moreira Sousa C, Lasgi C, Morin X and Humbert S (2014). Huntingtin Regulates Mammary Stem Cell Division and Differentiation. Stem Cell Reports, 2, 491-506.
 

Ben M’Barek K, Pla P, Orvoen S, Benstaali, Godin JD, Gardier AM, Saudou F, David DJ and Humbert S (2013). Huntingtin Mediates Anxiety/Depression-related Behaviors and Hippocampal Neurogenesis. J. Neurosci., 33, 8608-8620.
 

Moreira Sousa C, McGuire JR, Thion MS, Gentien D, de la Grange P, Tezenas du Montcel S., Vincent-Salomon A, Durr A and Humbert S (2013). The Huntington disease protein accelerates breast tumor development and metastasis through ErbB2/HER2 signaling. EMBO Mol. Med., 5, 309-325.
 

Godin JD, Colombo K, Molina-Calavita M, Keryer G, Zala D, Charrin BC, Dietrich P, Volvert ML, Guillemot F, Dragatsis I, Bellaiche Y, Saudou F, Nguyen L and Humbert S (2010). Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron, 67, 392-406.

 

  • Fabienne AGASSE
  • Barbara BRAZ
  • Laetitia CAPELLANO
  • Jean-Christophe DELOULME
  • Eric DENARIER
  • Dominique DIVERS PROIETTO
  • Sandrine HUMBERT
  • Rayane KASSEM
  • Sophie LENOIR
  • Leslie RATIE
  • Nathalie SCHER

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