Introduction: Our aim is to characterise stem cells and their daughters during embryonic and postnatal development of skeletal muscle to understand how this tissue is established, and how it regenerates during disease, and after injury. We are examining the genetic networks which regulate myogenic stem cell birth, and relating this to how cell order is established in this lineage. We are also investigating how stem/progenitor cells self-renew, essentially via symmetric vs. asymmetric cell divisions, and how the stem cell niche is defined.
Background: The myogenic determination genes Myf5, MyoD and Mrf4, as well as the paired/ homeodomain genes Pax3 and Pax7, mark skeletal muscle stem and progenitor cells. Using mouse mutants, we established epistatic relationships between these key regulators, and spatiotemporally uncoupled lineage progression to identify stem and progenitor cells in the embryo (1, 2). In adult muscle, we showed that the cell fate determinant Numb segregates asymmetrically during satellite cell divisions. Intriguingly, "immortal" template DNA strand cosegregation also occurs in vivo and in vitro. (3). Transcription factors are also distributed asymmetrically during division in this system.
Objectives: 1) Genetic regulation and lineage. We have generated multiple alleles in Myf5 and Pax7 to examine stem cells and their niche in the embryo and postnatally. These studies aim to link the embryonic muscle stem/founder cells with the principal postnatal regenerative stem cell, the satellite cell. We aim to distinguish stem from progenitor cells in muscle and study their respective roles in muscle growth and regeneration. Microarray studies using GFP knock-ins are designed to identify other novel regulators of this lineage.
2) Stem cell properties, self-renewal, and niche. Asymmetric cell divisions and the role of the niche, are being examined to determine how stem cells self-renew and differentiate. We are also studying the mechanism of template DNA strand cosegregation in the context of stem cell biology, cancer and epigenetic regulation.

3) Regenerative myogenesis. Another aim is to isolate and characterise mouse and human stem cells and examine their function in reconstitution assays by transplantations into injured dystrophic or normal muscles. We are investigating the roles of Pax7 and the myogenic determination genes in this context. Using genetically modified mice and specific markers, we are examining the anatomy of the muscle niche and how this may maintain the stem cell state. Collectively, these studies should provide a link between the normal development of a tissue, its deregulation during disease, and its regeneration via the recruitment of stem and progenitor cells.

References: 1) Kassar-Duchossoy et al. (2005). Genes & Dev. 2) Tajbakhsh (2005) Exp. Cell. Res. 3) Shinin et al. (2006). Nature Cell Biology.

Keywords: stem cells, asymmetric cellular division, skeletal muscle, somites, satellite cells, Myf5, MyoD, Mrf4, Pax3, Pax7, Numb, “immortal” template DNA strands

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. Nat Cell Biol 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.