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Nathalie Spassky

Cilia biology and neurogenesis

Our goal is to unravel the cellular and molecular mechanisms of neural stem cell biology. Neural stem cells are self-renewing multipotent progenitors, which can be used to replace neurons in degenerated or diseased nervous systems. However, many questions must be answered before neuronal replacement therapies using endogenous precursors become a reality. In particular, it is still unknown how the stem cell integrates the multiple signals from the environment that are responsible for its division, differentiation and survival. The existence of the primary cilium as a common feature of neural stem cells throughout life, and its location at the interface between the cytoplasm and the cerebral ventricle makes it a key organelle for the reception of such signals. Recent findings reveal that it is an antenna displaying specific receptors and relaying signals from these receptors to the cell body. Our goal is to understand the putative functions of the neural stem cell primary cilium during neurogenesis to provide new insights into the biology of neurogenesis and contribute to the development of new repair therapies.

We have shown that the neural stem cell primary cilium is crucial for proliferation in response to Sonic hedgehog (Shh) during development in both the cerebellum and hippocampus. Joubert syndrome (JS) is an auto- somal recessive disorder characterized by a distinctive cerebellar malformation. Identified mutated genes related to this disease encode centrosomal or ciliary proteins, suggesting that JS is a ciliopathy. To identify precisely the molecular mechanisms leading to cerebellar malformation, we have undertaken a detailed analysis of human cerebellar development in JS fetuses and controls. To further identify the functions of neural stem cell primary cilia in Shh-independent territories, we have generated conditional mutant mice in which cortical neuroepithelial cells lack primary cilia from E9,5. Another line of research focuses on multiciliated ependymal cells lining the cerebral ventricles. Coordinated beating of their cilia is crucial to propel cerebrospinal fluid secreted by the choroid plexus. We have shown that these cells are derived from radial glial cells and that a coupling between hydro- dynamic forces and the planar cell polarity pathway is required to orient ciliary beating during development. Through interdisciplinary efforts with physics and medical groups in Paris, we aim to bridge the gap between intraventricular mechanisms and pathology and repair in neurodegenerative diseases.

l Jord A, Shihavuddin A, Servignat d’Aout R, Faucourt M, Genovesio A, Karaiskou A, Sobczak-Thépot J, Spassky N and Meunier A. (2017) Calibrated mitotic oscillator drives motile ciliogenesis. Science 358 (6364):803-806.

A. Shihavuddin, S. Basu, E. Rexhepaj, F. Delestro, N. Menezes, SM. Sigoillot, E. del Nery, F. Selimi, N. Spassky and A. Genovesio. (2017) Smooth 2D manifold extraction from 3D image stack. Nature Communications. 31(8):15554.

N. Spassky and A. Meunier. (2017) The development and functions of multiciliated epithelia. Nat Rev Mol Cell Biol. 18(7):423-436. Review

P. Foerster, M. Daclin, S. Asm, M. Faucourt, A. Boletta, A. Genovesio and N. Spassky. (2017) mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis. Development. 144(2):201-210.

A. Meunier and N. Spassky. (2016) Centriole continuity: out with the new, in with the old. Curr Opin Cell Biol. 38:60-7. Review

A. Jourdon, A. Gresset, N. Spassky, P. Charnay, P. Topilko, and R. Santos. (2016) Prss56, a novel marker of adult neurogenesis in the mouse brain. Brain Struct Funct. 221(9):4411-4427.

A. Al Jord, N. Spassky, A. Meunier. (2015) Centriole amplification ? #DaughterCentriole. Med/Sci 31(3) :250-3. Review

N. Delgehyr, A. Meunier, M. Faucourt, M. Bosch Grau, L. Strehl, C. Janke and N. Spassky. (2015) Ependymal cell differentiation, from monociliated to multiciliated cells. Methods Cell Biol 127 :19-35.

N. Delgehyr & N. Spassky. Interplay between primary cilia and cell cycle. (2014) Med/Sci 30(11) :976-9. Review

A. Al Jord, A.I. Lemaitre, N. Delgehyr, M. Faucourt, N. Spassky# and A. Meunier#. (2014) Centriole amplification by mother and daughter centrioles differs in multiciliated cells. Nature 516(7529)104-7 (co-corresponding and co-last author).

M.B. Grau, G. Gonzalez Curto, C. Rocha, M.M. Magiera, P. Marques, T. Giordano, N. Spassky# and C. Janke#. (2013) Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia. J Cell Biol 202(3):441-51. (co-corresponding and co-last author)

A. Meunier, K. Sawamoto, and N. Spassky. (2013) Ependyma, choroid. Chapter 86 : Comprehensive Developmental Neuroscience. D. Rowitch and A. Alvarez-Buylla editors. Elsevier.

N. Spassky. (2013). Motile cilia and brain functions : ependymal motile cilia development, organization, function and their associated pathologies. K. Tucker and T. Caspary editors, Springer.

A. Aguilar, A. Meunier, L. Strehl, J. Martinovic, M. Bonniere, T. Attie-Bitach, F. Encha-Razavi and N. Spassky. (2012). Analysis of human samples reveals impaired Shh-dependent cerebellar development in Joubert syndrome/Meckel syndrome. PNAS 109(42) :16951-6.

B. Guirao, A. Meunier, S. Mortaud, A. Aguilar, J.M. Corsi, L. Strehl, Y. Hirota, A. Desoeuvre, C. Boutin, Y.G. Han, Z. Mirzadeh, H. Cremer, M. Montcouquiol, K. Sawamoto, and N. Spassky. (2010). Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. Nat Cell Biol, 12(4) :341-50.

Collaborations:

J.P. Baudoin, L. Viou, P. S. Launay, C. Luccardini, S. Espeso, V. Kiyasova, T. Irinopoulou, C. Alvarez, J.P. Rio, T. Boudier, J.P. Lechaire, N. Kessaris, N. Spassky, and C. Métin (2012). Tangentially migrating neurons assemble a primary cilium that promotes their re-orientation to the cortical plate. Neuron, 76(6) :1108-22.

G. Keryer, JR. Pineda, G. Liot, J. Kim, P. Dietrich, C. Benstaali, K. Smith, FP. Cordelières, N. Spassky, RJ. Ferrante, I. Dragatsis, and F. Saudou. (2011). Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest 121(11) :4372-82.

Y. Hirota, A. Meunier, S. Huang, T. Shimozawa, O. Yamada, Y.S. Kida, M. Inoue, T. Ito, H. Kato, M. Sakaguchi, T. Sunabori, M.A. Nakaya, S. Nonaka, T. Ogura, H. Higuchi, H. Okano, N. Spassky, and K. Sawamoto. (2010). Planar polarity of multiciliated ependymal cells involves the anterior migration of basal bodies regulated by non-muscle myosin II. Development 137(18):3037-46.

A. Molla-Herman, R. Ghossoub, T. Blisnick, A. Meunier, C. Serees, F. Silbermann, C.D. Emmerson, K. Romeo, P. Bourdoncle, A. Schmitt, S. Saunier, N. Spassky, P. Bastin, and A. Benmerah. (2010). The ciliary pocket: an endocytic membrane domain at the base of primary and motile cilia. J Cell Sci, 123 :1785-95.