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Abstract: Skeletal muscle satellite cells play a critical role during muscle growth, homoeostasis and regeneration. Selective induction of the muscle determination genes Myf5, Myod and Mrf4 during prenatal development can potentially impact on the reported functional heterogeneity of adult satellite cells. Accordingly, expression of Myf5 was reported to diminish the self-renewal potential of the majority of satellite cells. In contrast, virtually all adult satellite cells showed antecedence of Myod activity. Here we examine the priming of myogenic cells by Mrf4 throughout development. Using a Cre-lox based genetic strategy and novel highly sensitive Pax7 reporter alleles compared to the ubiquitous Rosa26-based reporters, we show that all adult satellite cells, independently of their anatomical location or embryonic origin, have been primed for Mrf4 expression. Given that Mrf4 Cre and Mrf4 nlacZ are active exclusively in progenitors during embryogenesis, whereas later expression is restricted to differentiated myogenic cells, our findings suggest that adult satellite cells emerge from embryonic founder cells in which the Mrf4 locus was activated. Therefore, this level of myogenic priming by induction of Mrf4, does not compromise the potential of the founder cells to assume an upstream muscle stem cell state. We propose that embryonic myogenic cells and the majority of adult muscle stem cells form a lineage continuum. [Copyright &y& Elsevier]

During organogenesis, a continuum of founder stem cells produces temporally distinct progeny until development is complete. Similarly, in skeletal myogenesis, phenotypically and functionally distinct myoblasts and differentiated cells are generated during development. How this occurs in muscle and other tissues in vertebrates remains largely unclear. We showed previously that committed cells are required for maintaining muscle stem cells. Here we show that active Notch signalling specifies a subpopulation of myogenic cells with high Pax7 expression. By genetically modulating Notch activity, we demonstrate that activated Notch (NICD) blocks terminal differentiation in an Rbpj-dependent manner that is sufficient to sustain stem/progenitor cells throughout embryogenesis, despite the absence of committed progeny. Although arrested in lineage progression, NICD-expressing cells of embryonic origin progressively mature and adopt characteristics of foetal myogenic cells, including expression of the foetal myogenesis regulator Nfix. siRNA-mediated silencing of NICD promotes the temporally appropriate foetal myogenic fate in spite of expression of markers for multiple cell types. We uncover a differential effect of Notch, whereby high Notch activity is associated with stem/progenitor cell expansion in the mouse embryo, yet it promotes reversible cell cycle exit in the foetus and the appearance of an adult muscle stem cell state. We propose that active Notch signalling is sufficient to sustain an upstream population of muscle founder stem cells while suppressing differentiation. Significantly, Notch does not override other signals that promote temporal myogenic cell fates during ontology where spatiotemporal developmental cues produce distinct phenotypic classes of myoblasts. [ABSTRACT FROM AUTHOR]

Skeletal muscle stem cell fate in adult mice is regulated by crucial transcription factors, including the determination genes Myf5 and Myod. The precise role of Myf5 in regulating quiescent muscle stem cells has remained elusive. Here we show that most, but not all, quiescent satellite cells express Myf5 protein, but at varying levels, and that resident Myf5 heterozygous muscle stem cells are more primed for myogenic commitment compared with wild-type satellite cells. Paradoxically however, heterotypic transplantation of Myf5 heterozygous cells into regenerating muscles results in higher self-renewal capacity compared with wild-type stem cells, whereas myofibre regenerative capacity is not altered. By contrast, Pax7 haploinsufficiency does not show major modifications by transcriptome analysis. These observations provide a mechanism linking Myf5 levels to muscle stem cell heterogeneity and fate by exposing two distinct and opposing phenotypes associated with Myf5 haploinsufficiency. These findings have important implications for how stem cell fates can be modulated by crucial transcription factors while generating a pool of responsive heterogeneous cells. [ABSTRACT FROM AUTHOR]

Abstract: Development and maintenance of an abundant tissue such as skeletal muscle poses several challenges. Curiously, not all skeletal muscle stem cells are born alike, since diverse genetic pathways can specify their birth. Stem and progenitor cells that establish the tissue during development, those that maintain its homeostasis, as well as participate in its regeneration have generated considerable interest. The ability to distinguish stem cells from more committed progenitors throughout prenatal and postnatal life has guided researchers to identify stem cell properties and characterise their niche. These properties include markers that influence cell behaviour and mode of division during normal development, after trauma and cell transplantations. This review addresses these issues from a developmental perspective. [Copyright &y& Elsevier]