Introduction: Our aim is to characterize 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. Interestingly, these events are related and they can be executed independently of the niche (3).
Objectives: 1) Genetic regulation and lineage. We have generated new 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. These questions need to be resolved to distinguish stem from progenitor cells in muscle and study their respective roles in muscle growth and regeneration. Microarray screens using GFP knock-ins are designed to identify other novel regulators.
2) Stem cell properties, self-renewal, and niche. Different approaches, including asymmetric cell divisions and the role of the niche, are being used 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 stem cells, examine their properties, and study their behavior in functional reconstitution assays by engraftment into injured dystrophic or normal muscles. These models are well established and 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.