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Grenoble Institut des Neurosciences

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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.

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.

Research themes and techniques used

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

Major publications :

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.

Barnat M, Le Friec J, Benstaali C, Humbert S (2017). Huntingtin-mediated Multipolar-Bipolar Transition of Newborn Cortical Neurons is Critical for their Postnatal Neuronal Morphology. Neuron, 93, 99-114.

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.

Thion MS, Tézenas du Montcel S, Golmard JL, Vacher S, Barjhoux L, Sornin V, Cazeneuve C, Bièche I, Sinilnikova O and Stoppa-Lyonnet D for GEMO, Durr A, Humbert S (2016). CAG repeat size in Huntingtin alleles predicts cancer prognosis. EJHG, 24, 1310-1315.

Thion MS, McGuire JR, Sousa CM, Fuhrmann L, Fitamant J, Leboucher S, Vacher S, Tezenas du Montcel S, Bièche I, Bernet A, Mehlen P, Vincent-Salomon A, 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, 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, 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, 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, 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, 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, Humbert S (2010). Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron, 67, 392-406.