Régulation de la dynamique des microtubules et de leurs fonctions

Leader

Research center

26 rue d'Ulm
75005 Paris

Institution

CNRS
Institut Curie
Université Paris Sud 11
Cellules Genes Genomes
Université Paris Sud

Laboratory

Phone: 0169863127
UMR3348
Labex CelTisPhyBio

Keywords

Neurodegeneration
tubulin code
microtubule cytoskeleton
posttranslational modifications
neuronal differentiation
Available to host a PhD student

Publications

Rocha C, Papon L, Cacheux W, Marques Sousa P, Lascano V, Tort O, Giordano T, Vacher S, Lemmers B, Mariani P, Meseure D, Medema JP, Bièche I, Hahne M, Janke C (2014) Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon. EMBO J 33: 2247-2260

Janke C (2014) The tubulin code: Molecular components, readout mechanisms, and functions. J Cell Biol 206: 461-472

Bosch Grau M, Gonzalez Curto G, Rocha C, Magiera MM, Marques Sousa P, Giordano T, Spassky N, Janke C (2013) Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia. J Cell Biol 202: 441-451

Rogowski K, van Dijk J, Magiera MM, Bosc C, Deloulme J-C, Bosson A, Peris L, Gold ND, Lacroix B, Bosch Grau M, Bec N, Larroque C, Desagher S, Holzer M, Andrieux A, Moutin M-J, Janke C (2010) A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell 143: 564-578

Lacroix B, van Dijk J, Gold ND, Guizetti J, Aldrian-Herrada G, Rogowski K, Gerlich DW, Janke C (2010) Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. J Cell Biol 189: 945-954
Janke C, Kneussel M (2010) Tubulin post-translational modifications: encoding functions on the neuronal microtubule cytoskeleton. Trends Neurosci 33: 362-372

Rogowski K, Juge F, van Dijk J, Wloga D, Strub J-M, Levilliers N, Thomas D, Bré MH, Van Dorsselaer A, Gaertig J, Janke C (2009) Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation. Cell 137: 1076-1087

Maas C, Belgardt D, Lee HK, Heisler FF, Lappe-Siefke C, Magiera MM, van Dijk J, Hausrat TJ, Janke C, Kneussel M (2009) Synaptic activation modifies microtubules underlying transport of postsynaptic cargo. Proc Natl Acad Sci U S A 106: 8731-8736

Janke C, Rogowski K, Wloga D, Regnard C, Kajava AV, Strub J-M, Temurak N, van Dijk J, Boucher D, van Dorsselaer A, Suryavanshi S, Gaertig J, Eddé B (2005) Tubulin polyglutamylase enzymes are members of the TTL domain protein family. Science 308: 1758-1762

Fields of research

Neurogenetics / neurodevelopment

Research Theme

In our ongoing projects, we are using biochemistry, biophysics and structural biology in conjunction with cell and mouse biology to identify the molecular mechanisms by which tubulin posttranslational modifications regulative microtubule behaviour and functions, and which are the cellular and developmental roles of these modifications and the corresponding enzymes. Our functional studies are focussed on the nervous system, cilia and flagella (including spermatogenesis), and cell division. Our team is closely collaborating with clinicians to delineate the implications of tubulin posttranlsational modifications in human pathologies.  

Microtubules are key cytoskeletal elements involved in a large number of functions in eukaryotic cells. They assemble from a protein dimer of a- and b-tubulin, two highly similar and conserved proteins. Tubulins are subject to a large variety of posttranslational modifications, which provide a rapid and reversible mechanism to diversify microtubule functions in cells. Our team is studying the mechanisms and functional roles of these modifications by using an interdisciplinary approach.

Our team has identified the enzymes involved in the posttranslational polyglutamylation (Janke et al, 2005; van Dijk et al, 2007), deglutamylation (Rogowski et al, 2010; Tort et al, 2014) and polyglycylation (Rogowski et al, 2009) of tubulin. Following the discovery of these enzymes, we are now investigating (i) the molecular mechanisms, and (ii) the biological functions of tubulin-modifying enzymes.

Polyglutamylation and polyglycylation take place within the C-terminal tails of the tubulin molecules. These tails are localized at the outer surface of the microtubule, thus their posttranslational modification is most likely regulating the interactions of microtubules with their multiple binding partners, commonly known as microtubule-associated proteins (MAPs) and molecular motors. So far we have demonstrated that the microtubule-severing protein spastin is regulated by tubulin polyglutamylation (Lacroix et al, 2010), and that tubulin glycylation stabilizes ciliary axonemes by a yet unknown molecular mechanism (Bosch Grau et al, 2013; Rogowski et al, 2009). Our functional studies have demonstrated an important role for both, polyglutamylation and polyglycylation for motile and primary cilia in mammals (Bosch Grau et al, 2013; Rocha et al, 2014), and we have found that polyglutamylation is directly linked to neurodegeneration in mice (Rogowski et al, 2010). We have further demonstrated a direct link between altered levels of a tubulin glycylase and colorectal cancer development (Rocha et al, 2014).

Team members

Annemarie Wehenkel
Cecilia Serieyssol
Kathiresan Natarajan
Laurence Vaslin
Maria Magiera
Ngoc-Lan Julie Nguyen
Sudarshan Gadadhar
Tiziana Giordano
Lurlene Akendengue

Lab rotation

Posttranslational modifications of microtubules to control axonal transport

Team leader: 

JANKE Carsten

Dates: 

January 2, 2018 - June 29, 2018

Application deadline: 

June 29, 2018

Period

~ Jan-March 2018

~ April-June 2018

Project

Polyglutamylation is a posttranslational modification of microtubules, expected to regulate the axonal traffic in neurons. The goal of this rotation is to study the impact of polyglutamylation on axonal traffic using primary hippocampal neurons polyglutamylation-altered mouse lines by live cell imaging.

Contact

Institut Curie - Centre Universitaire, Batiment 110, 91405 Orsay Cedex - +33 1 69 86 31 27 - Maria.Magiera@curie.fr

Supervisor: 

MAGIERA Maria