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Wednesday, October 31st, 2018
From 11h30 To 12h30
Centre de Recherche - Paris - Amphithéâtre Hélène Martel-Massignac

The nuclear-cytoskeleton connection and nuclear positioning during muscle formation.

Muscle cells are characterized by the presence of multiple nuclei evenly spaced under the plasma membrane. Whether this particular arrangement is required for muscle function is still under debate. Nonetheless, several muscular diseases are characterized by abnormal nuclear positioning, such as centronuclear myopathies, titinopathies and desminopathies or due to mutations of nuclear envelope proteins known to be involved in nuclear movement in other systems. The position of nuclei could be important for proper distribution of mRNA and proteins in such large cells. We have, since several years, investigated the mechanisms controlling three of the four different and successive nuclear movements occurring during myofiber formation through live imaging. We have developed cell systems which can achieve myofiber maturation, with peripheral nuclei and presence of triads and sarcomeres. By screening the effect of different molecular motors deletion, we have identified several microtubule-associated motors implicated at different levels on nuclear movement and positioning. We have established the connection between the nucleus and the cytoskeleton to be decisive for proper nuclear positioning. In particular, Nesprin-1, a protein mutated in congenital muscular dystrophy, is required for the reorganization of the microtubule cytoskeleton during the differentiation of muscle cells and the subsequent nuclear movements. Anchored to the nuclear envelope, Nesprin-1 is part of the LINC complex, making the link between the cytoskeleton and the lamins inside the nucleus. Our research using in vitro systems recapitulates in vivo observations and allow the study of the impact of mutations found in muscular diseases on nuclear positioning in muscle cells.


Bruno Cadot

Center for Research in Myology, Sorbonne Université

Invited by

Cécile Sykes
Pascal Silberzan

Learn more

. Cadot B. La différenciation des cellules musculaires striées squelettiques. Planet-Vie, Jeudi 28 juin 2018 Link

. Cadot B. Editorial: Nuclear positioning: a matter of life. Semin Cell Dev Biol (2017), https://doi.org/10.1016/j.semcdb.2017.11.034. 

. Inserm newsletter: link

. Gimpel P, Lee YL, Sobota RM, Calvi A, Koullourou V, Patel R, Mamchaoui K, Nédélec F, Shackleton S, Schmoranzer J, Burke B, Gomes ER, Cadot B. Nesprin-1α-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells. Current Biology. 2017 Sep 27 pii: S0960-9822(17)31069-2. doi: 10.1016/j.cub.2017.08.031. LinkCited 22 times.

. Roman W, Martins JP, Carvalho FA, Voituriez R, Abella JVG, Santos NC, Cadot B, Way M, Gomes ER. Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle. Nature Cell Biology.  2017 Sep 11. doi: 10.1038/ncb3605Link Cited 17 times.
. Gomes ER & Cadot B. Molecular Motors and Nuclear Movements in Muscle. Article Addendum. Communicative & Integrative Biology. 2017. Link

. Gache V, Gomes ER, Cadot B. Molecular motors involved in nuclear movement during skeletal muscle differentiationMolecular Biology of the Cell. April 1, 2017 vol. 28 no. 7 865-874. Link Cited 11 times.

. Pimentel M., Falcone S., Cadot B., Gomes ER. Isolation of Mouse Myoblasts for Differentiation and Imaging of Mature MyofibersJ. Vis. Exp. 2016 e55141, doi:10.3791/55141. Link Cited 4 times.

. Vilmont V., Cadot B., Ouanounou G, Schmitt A, Gomes ER. A system for studying mechanisms of neuromuscular junction development and maintenance. Development. 2016 Jul 1;143(13):2464-77. Link Cited 7 times.
. Vilmont V., Cadot B., Vezin E, Le Grand F, Gomes ER. Dynein disruption perturbs post-synaptic components and contributes to impaired MuSK clustering at the NMJ: implication in ALS. Scientific Reports. 2016 Jun 10;6:27804. Link Cited 7 times.
.Cadot B, Gache V, Gomes ER. Moving and positioning the nucleus in skeletal muscle – one step at a timeNucleus. 2015 Sept link. (Corresponding author) Link Cited 28 times.

.Zalc A., Rattenbach R., Auradé F., Cadot B., Relaix F. Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defectsDevelopmental Cell. 2015 Apr 6;33(1):56-66. Link Cited 15 times.

.Cadot B, Gomes ER. Skeletal muscleEncyclopedia of Cell Biology. 2016 Elsevier, Pages 677–682 Link

.Cadot B, Gache V, Gomes ER. Fast, multi-dimensional and Simultaneous Kymograph-like Particle dynamics (SkyPad) analysis.PlosOne. 2014 Feb 19;9(2):e89073. (Corresponding author) Link Cited 1 times.

·Cadot B, Gache V, Gomes ER. Spatial distribution of nuclei in muscle fibers: a novel actor of muscular functionMed Sci (Paris). 2012 Jun-Jul;28(6-7):577-9. Link

·Cadot B, Gache V, Vasyutina E, Falcone S, Birchmeier C, Gomes ER. Nuclear movement during myotube formation is microtubule and dynein dependent and is regulated by Cdc42, Par6 and Par3EMBO Rep. 2012 Aug 1;13(8):741-9. Link Cited 74 times

·Metzger T, Gache V, Xu M, Cadot B, Folker ES, Richardson BE, Gomes ER, Baylies MK. MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function. Nature. 2012 Mar 18;484(7392):120-4. Link Cited 140 times

· Rufini S, Lena AM, Cadot B, Mele S, Amelio I, Terrinoni A, Desideri A, Melino G, Candi E. The sterile alpha-motif (SAM) domain of p63 binds in vitro monoasialoganglioside (GM1) micellesBiochem Pharmacol. 2011 Nov 15;82(10):1262-8. doi: 10.1016/j.bcp.2011.07.087. Cited 15 times.

·Mitchell KJ, Pannérec A, Cadot B, Besson V, Palakian A, Gomes E, Marazzi G and David Sassoon. Identification and characterisation of a non-satellite cell resident muscle progenitor during postnatal developmentNat Cell Biol 2010 Mar;12(3):257-66. Link
Cited 317 times

·Cadot B., Brunetti B., Coppari S., Fedeli S., de Rinaldis E, Claudio dello Russo, Gallinari P., De Francesco R., Steinkühler C. and Filocamo G. Loss of HDAC4 causes segregation defects during mitosis of p53-deficient human tumor cellsCancer Research. 2009;69(15):6074-82. Cited 23 times.

·Cicero, DO., Falconi, M., Candi, E., Mele, S., Cadot, B., Di Venere, A., Rufini, S., Melino, G., Desideri (2006). NMR structure of the p63 SAM domain and dynamic properties of G534V and T537P pathological mutantsCell Biochemistry and Biophysics.2006;44(3):475-89. Cited 26 times.

·Cadot, B., Rufini, A., Pietroni, V., Ramadan, S., Guerrieri, P., Melino, G., Candi, E. (2004) Overexpressed transglutaminase 5 triggers cell deathAmino Acids. Jul;26(4):405-8. Cited 3 times.

·Terrinoni, A., Ranalli, M., Cadot, B., Leta, A., Bagetta, G., Vousden, K.H., Melino, G. (2004) p73-alpha is capable of inducing scotin and ER stressOncogene. Apr 29;23(20):3721-5. Cited 66 times.

·Candi, E., Paradisi, A., Terrinoni, A., Pietroni, V., Oddi, S., Cadot, B., Jogini, V., Meiyappan, M., Clardy, J., Finazzi-Agro, A., Melino, G. (2004) Transglutaminase 5 is regulated by guanine-adenine nucleotidesBiochem J. Jul 1;381(Pt 1):313-9. Cited 60 times.

·Candi E., Paradisi A., Terrinoni A., Cadot B., Rufini A., Puddu P., Melino G. (2002) Role of Transglutaminase 5 in epidermisMinerva Biotec. 14: 155-158.

·Glukhova, L., Angevin, E., Lavialle, C., Cadot, B., Terrier-Lacombe, M.J., Perbal, B., Bernheim, A., Goguel, A.F. (2001) Patterns of specific genomic alterations associated with poor prognosis in high-grade renal cell carcinomasCancer Genet Cytogenet. Oct 15;130(2):105-10. Cited 61 times

·Cadot, B., Maillard, M., Ball, R.Y., Sethia, K., Edwards, D.R., Perbal, B., Tatoud, R. (2001) Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissuesMol Pathol. Aug;54(4):275-80. Cited 78 times