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. We are examining the genetic networks which regulate myogenic stem cell emergence, 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 paired/ homeodomain genes Pax3 and Pax7, and the myogenic determination genes Myf5, Myod and Mrf regulate skeletal muscle stem and progenitor cell fates. Using mouse mutants, we established epistatic relationships between these key regulators, and spatiotemporally uncoupled lineage progression (1). We showed also that extraocular myogenic fate is regulated largely by Myf5 and Mrf4 whereas pharyngeal myogenesis is severely impaired in Tbx1:Myf5 double mutants. Thus, complementary pathways, governed by Pax3 in body, and Tbx1, in pharyngeal muscles, but absent in extraocular muscles, activate the core myogenic network for initiating myogenesis (2). In adult muscle, intriguingly, biased DNA strand segregation occurs in vivo and in vitro (3). Transcription factors are also distributed asymmetrically during satellite cell division in this system.
Objectives: 1) Genetic regulation and lineage. Genetic mutants for Myf5, Pax7, Myod, Tbx1, RBPJk, Numb, Numblike in combination with Cre driver and fluorescent reporter mice are used to examine muscle stem cell regulation in the embryo and postnatally in the context of normal growth and after injury during regeneration. Developmental microarrays and miRNA screens have been done using GFP knock-ins to identify novel regulators.
2) Stem cell properties, self-renewal, and niche. Asymmetric cell divisions are being examined. We are also studying the mechanism of template DNA strand cosegregation to understand how this phenomenon relates to stem cells and epigenetic regulation.

3) Regenerative myogenesis. We also isolate and characterise mouse and human stem cells and examine their function in reconstitution assays by transplantations into injured dystrophic or normal muscles. Using genetically modified mice and specific markers, we are examining cell-cell interactions in the muscle niche. 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) Sambasivan et al. (2009) Dev. Cell; 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

Nowlan, N.C. C. Bourdon, G. Dumas, S. Tajbakhsh, P.J. Prendergast and P. Murphy. (2010) Developing Bones are Differentially Affected by Compromised Skeletal Muscle Formation. Bone. 46: 1275-85.

Brigitte, M., Schilte, C., Plonquet, A., Baba-Amer, Y., Henri, A., Charlier, C., Tajbakhsh, S., Albert, M., Gherardi, R. K. and Chretien, F. (2010). Muscle resident macrophages control the immune cell reaction in a mouse model of notexin-induced myoinjury. Arthritis Rheum 62, 268-279.

Theis S, Patel K, Valasek P, Otto A, Pu Q, Harel I, Tzahor E, Tajbakhsh S, Christ B, Huang R. (2010). The occipital lateral plate mesoderm is a novel source for vertebrate neck musculature. Development 137:2961-2971.

Tajbakhsh S. (2010). Comment percer les mystères de la ségrégation asymétrique de lADN pendant la mitose. Unravelling the mysteries of biased DNA segregation during mitosis. Médecine/Sciences, 26(8-9):696-8.