Stem Cells and Development (URA CNRS 2578)

Shahragim Tajbakhsh

Establishing the skeletal muscle lineage

How do stem cells self-renew and establish skeletal muscle during embryonic and fœtal development, and in the adult (1)? We have developed unique genetic tools by knock-ins and transgenesis to address this issue in the mouse.

Specification and determination of skeletal muscle

We showed previously that Pax3 and Myf5 are key transcription factors acting genetically upstream of Myod to establish skeletal muscle in the body (1). More recently, our work has extended these observations and lead to a revision of the long standing view that Myf5 and Myod are the only determination genes in this lineage in mice. Unexpectedly, Mrf4 which was previously described as a differentiation gene, acts as a determination gene in vivo. Consequently, Mrf4:Myf5:Myod triple mutants are required to eliminate all skeletal muscle in the mouse (2). Importantly, the new Myf5:Myod double mutants permit us to genetically uncouple embryonic from fœtal myogenesis and ask how skeletal muscle stem and progenitor cells which are marked by Pax3 and Pax7 expression, self-renew and regulate this lineage.

Asymmetric cell divisions and stem cell self-renewal

One mechanism governing stem cell self-renewal involves asymmetric cell divisions. Using live imaging and videomicroscopy in combination with immunochemistry of the cell fate choice determinant Numb, we show that asymmetric cell divisions take place in primary cultures of adult satellite cell derived myoblasts. We postulate that these events are also taking place in this lineage during embryonic and fœtal development and we are examining this phenomenon using various knock-in and transgenic tools. These genetically manipulated mice are also used to investigate how stem to differentiated cell transitions are regulated and how homeostasis is achieved in skeletal muscle.

Selected Publication from 2004


Kassar-Duchossoy, L., Gayraud-Morel, B., Gomès, D., Rocancourt, D., Buckingham, M., Shinin, V., Tajbakhsh, S. (2004). Mrf4 determines skeletal muscle identity in Myf5 :MyoD double mutant mice. Nature, 431: 466-471.
Kassar-Duchossoy, L., Giacone, E., Gayraud-Morel, B., Jory, A., Gomès, D., Tajbakhsh, S. (2005). Pax3/Pax7 mark a novel population of primitive myogenic cells during development. Genes & Dev., 3:1426-1431.
Shinin, V., Gayraud-Morel, B., Gomes, D., and Tajbakhsh, S. (2006). Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biology, 8, 677-82.
Gayraud-Morel, B., F. Chrétien, P. Flamant, D. Gomès, P.S. Zammit, and S. Tajbakhsh (2007). A role for the myogenic determination gene Myf5 in adult regenerative myogenesis. Dev Biol., 312:13-28 Epub 2007 Sep 11.
Cossu G, Tajbakhsh S. (2007). Oriented cell divisions and muscle satellite cell heterogeneity. Cell, 129(5):859-61.
Gayraud-Morel, B., F. Chrétien and S. Tajbakhsh (2009). Skeletal muscle as a paradigm for regenerative biology and medicine. Regenerative Medicine, 4:293-319.
Sambasivan, R., B. Gayraud-Morel, G. Dumas, C. Cimper, S. Paisant, R. G. Kelly and S. Tajbakhsh (2009). Distinct regulatory cascades govern extraocular and pharyngeal arch muscle progenitor cell fates. Developmental Cell, 16: 810-821.
Tajbakhsh, S. (2009). Stem cell: what's in a name? Nature Reports Stem Cells, June 25.
Jory, A., Le Roux, I., Gayraud-Morel, B., Rocheteau, Pierre, Cohen-Tannoudji, M., Cumano, A. and S. Tajbakhsh. (2009). Numb promotes progenitor cell self-renewal in the embryonic somite. Stem Cells, 27: 2769-2780.
Tajbakhsh S. (2009). Skeletal muscle stem cells in developmental versus regenerative myogenesis. J Intern Med., 266(4):372-89.
Tajbakhsh, S., Rocheteau, P., Le Roux, I.. (2009). Asymmetric cell divisions and asymmetric cell fates. Annual Reviews in Cell & Developmental Biology, 25:671-99.
Tajbakhsh, S. and C. Gonzales (2009). Biased segregation of DNA and centrosomes: moving together or drifting apart? Nature Reviews Molecular & Cellular Biology, 10: 804-810.
Sambasivan, R., Kuratani, S. and Tajbakhsh, S. (2011). An eye on the head: the development and evolution of craniofacial muscles. Development, 138: 2401-15.
Sambasivan# R, Yao# R, Kissenpfennig A, Van Wittenberghe L, Paldi A, Gayraud-Morel B, Guenou H, Malissen B, Tajbakhsh S*, Galy A*. (2011). Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development, 138: 3647-3656.
          # equal contributing authors; * co-corresponding authors
Dellavalle, A., G. Maroli, D. Covarello, E. Azzoni1,, A. Innocenzi, L. Perani, S.Antonini, R. Sambasivan, S. Brunelli, S. Tajbakhsh and G. Cossu (2011). Pericytes resident in post-natal skeletal muscle differentiate into muscle fibers and enter the satellite cell pool. Nature Communications, 2:499.
Mourikis, P. R. Sambasivan, D. Castel, P. Rocheteau, V. Bizzarro and S. Tajbakhsh (2012). A critical requirement for Notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells, 30: 243-252.
Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. and S. Tajbakhsh (2012). A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell, 48: 112-125.
Gayraud-Morel, B., F. Chrétien, A. Jory,R. Sambasivan, E. Negroni, P. Flamant, G. Soubigou, J.-Y. Coppée, J. Di Santo, A. Cumano, V. Mouly, and S. Tajbakhsh (2012).Haploinsufficiency of Myf5 reveals distinct cell fate potentials for adult skeletal muscle stem cells, J. Cell Science, 125: 1738-1749.
Lathil, M., P. Rocheteau, L. Châtre, S. Sanulli, S. Memet, M. Ricchetti, S. Tajbakhsh#, and F. Chrétien# (2012). Skeletal muscle stem cells adopt a dormant state post mortem and retain regenerative capacity. Nature Communications, June 12; 3: 903
          # equal contributing authors
Fabien Le Grand, R. Grifone, P. Mourikis, C. Houbron, C. Gigaud, J. Pujol, M. Maillet, G. Pagès, M. Rudnicki, S. Tajbakhsh and P. Maire (2012). Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration J. Cell Biology, 198: 815-832.
Mourikis, P., S. Gopalakrishnan, R. Sambasivan and S. Tajbakhsh (2012). Cell-autonomous Notch activity maintains the temporal specification potential of skeletal muscle stem cells Development, 139: 4536-4538.
Tajbakhsh, S. (2013) Losing stem cells in the aged skeletal muscle niche Cell Research 4:455-457.
Castel*, D., P. Mourikis*, S. Bartels*, A.B. Brinkman, S. Tajbakhsh#, H.G. Stunnenberg# (2013).  Dynamic binding of RBPJ is determined by Notch signalling status. Genes & Development 27(9):1059-71;* equal contribution; #co-corresponding
Sambasivan, R., G. Comai*, I. Le Roux*, D. Gomès, J. Konge, G. Dumas, C. Cimper and S. Tajbakhsh (2013). Embryonic founders of adult muscle stem cells are primed by the muscle determination gene Mrf4. Developmental Biology, 381:241-255; *equal contribution.
Evano, B. and S. Tajbakhsh (2013). Sorting DNA with asymmetry: a new player in gene regulation? Chromosome Research, 21:225-242.
Yennek, S. and S. Tajbakhsh (2013). DNA asymmetry and cell fate regulation in stem cells. Seminars in Cell & Developmental Biology, in press.
Lee, AS, J. Harris, M. Bate, K. Vijayraghavan, L. Fisher, S. Tajbakhsh, M. Duxson (2013). Initiation of primary myogenesis in amniote limb muscles. Dev. Dyn., 242:1043-55.