Martial Ruat Team

Signal Transduction & Developmental Neuropharmacology

In brief

Our group aims at deciphering the molecular and pharmacological mechanisms implicated in adult neural stem cells (NSCs) maintenance. We develop animal models to study NSCs and their progeny and chemical screening to identify novel innovative therapeutic strategies for brain repair and for treating brain tumors.

Our research

Research context and strategy

• In the adult brain, neural stem cells (NSCs) represent a reservoir of cells that could be potentially recruited to stimulate glio- and neurogenesis, and may therefore have a broad range of therapeutic applications for brain repair. Aberrant activation of signaling pathways in NSCs or in neural progenitors have been associated to brain tumors.

• We are using and developing conditional mouse models for studying adult NSCs and their progeny in the main neurogenic niches of the brain. We are focusing our work towards understanding the functional roles of the Hedgehog signaling pathway proposed to modulate the maintenance of adult neurogenic niches and to regulate the proliferation and differentiation of neuronal and glial precursors. We are currently analyzing modifications of this pathway such as those linked to human mutations responsible for the development of brain tumors such as medulloblastoma. The pharmacological treatment of these disturbances is investigated using synthetic molecules that we develop with organic and medicinal chemists.

• Thus, we have characterized and patented reference agonists and antagonists of the Smoothened receptor which mediates most of the effects of the Hedgehog signals. These molecules have potential interests in the treatment of demyelinating diseases and brain cancers. They should contribute to elucidate mechanisms regulating the maintenance of precursor cells that represent a major challenge for the discovery of effective treatments for neurodegenerative diseases and cancers.

Selected Publications

> Linda Tirou, Mariagiovanna Russo, Hélène Faure, Giuliana Pellegrino, Ariane Sharif, Martial Ruat. C9C5 positive mature oligodendrocytes are a source of Sonic Hedgehog in the mouse brain. PloS one, 2020, 15 (2), pp e0229362, (doi:10.1371/journal.pone.0229362)

> Chia-Hsiang Chang, Marco Zanini, Hamasseh Shirvani, Jia-Shing Cheng, Hua Yu, Chih-Hsin Feng, Audrey L. Mercier, Shiue-Yu Hung, Antoine Forget, Chun-Hung Wang, Sara Maria Cigna, I. Ling Lu, Wei-Yi Chen, Sophie Leboucher, Won-Jing Wang, Martial Ruat, Nathalie Spassky, Jin-Wu Tsai, Olivier Ayrault. Atoh1 Controls Primary Cilia Formation to Allow for SHH-Triggered Granule Neuron Progenitor Proliferation. Developmental Cell, 2019, 48 (2), pp 184-199.e185, (10.1016/j.devcel.2018.12.017) (hal-02020341v1)

> Alexandra Chicheportiche, Martial Ruat, François D. Boussin, Mathieu Daynac. Isolation of Neural Stem and Progenitor Cells from the Adult Brain and Live Imaging of Their Cell Cycle with the FUCCI System. Cellular Quiescence: Methods and Protocols 2018. New York, NY: Springer New York. p 69-78. (10.1007/978-1-4939-7371-2_5) (hal-01661733v1)

> Mathieu Daynac, Linda Tirou, Hélène Faure, Marc-André Mouthon, Laurent R. Gauthier, Heidi Hahn, François D. Boussin, Martial Ruat. Hedgehog Controls Quiescence and Activation of Neural Stem Cells in the Adult Ventricular-Subventricular Zone. Stem cell reports, 2016, 7 (4), pp 735-748, (10.1016/j.stemcr.2016.08.016) (hal-01373136v1)

> Audrey Fleury, Lucile Hoch, M. Carmen Martinez, Hélène Faure, Maurizio Taddei, Elena Petricci, Fabrizio Manetti, Nicolas Girard, André Mann, Caroline Jacques, Jérôme Larghero, Martial Ruat, Ramaroson Andriantsitohaina, Soazig Le Lay. Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway. Scientific Reports, 2016, 6 (1), pp 23479, (10.1038/srep23479) (hal-01304661v1)

> Lucile Hoch, Hélène Faure, Hermine Roudaut, Angele Schoenfelder, Andre Mann, Nicolas Girard, Laure Bihannic, Olivier Ayrault, Elena Petricci, Maurizio Taddei, Didier Rognan, Martial Ruat. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015, 29 (5), pp 1817-1829, (10.1096/fj.14-267849) (hal-01142537v1)

> Martial Ruat. Top Med Chem: The Smoothened Receptor in Cancer and Regenerative Medicine. 2015. Springer International Publishing. 1-210 p. (https://doi.org/10.1007/978-3-319-19755-5)

> Julien Ferent, Loic Cochard, Hélène Faure, Maurizio Taddei, Heidi Hahn, Martial Ruat, Elisabeth Traiffort. Genetic activation of Hedgehog signaling unbalances the rate of neural stem cell renewal by increasing symmetric divisions. Stem cell reports, 2014, 3 (2), pp 312-323, (10.1016/j.stemcr.2014.05.016) (hal-01142521v1)

Team members