How a continuum of founder stem cells generates distinct phenotypic classes of differentiating cells during organogenesis is a question of major interest in developmental biology. During Drosophila neuroblast divisions, the temporal expression of Pou

INTRODUCTION How a continuum of founder stem cells generates distinct phenotypic classes of differentiating cells during organogenesis is a question of major interest in developmental biology. During Drosophila neuroblast divisions, the temporal expression of Pou domain and zinc finger transcription factors governs the neural identity of daughter cells, which is subject to their spatial identity (Kambadur et al., 1998; Isshiki et al., 2001; Grosskortenhaus et al., 2006). Similarly, in the vertebrate CNS, radial glial cells generate distinct neurons that are spatially specified largely via an interplay between homeodomain and bHLH transcription factors (Maurange, 2012). Although less complex in terms of cellular diversity, little is known about the generation of distinct classes of committed progeny during vertebrate skeletal muscle development. Skeletal muscle founder stem cells in the body arise from a transient epithelial dermomyotome (DM) within somites and express the paired box/homeodomain transcription factors Pax3 and Pax7 (Ben-Yair and Kalcheim, 2005; Kassar-Duchossoy et al., 2005; Relaix et al., 2005). They undergo myogenic specification to give rise to muscle progenitor cells by sequential expression of the bHLH myogenic regulatory factors (MRFs) Myf5, Mrf4 (also known as Myf6) and Myod, and, subsequently, the differentiation gene myogenin (Myog) (Rudnicki et al., 1993; Kassar-Duchossoy et al., 2004; Tajbakhsh, 2009). During early embryonic stages, Pax7 marks bi-potent cells in the DM that can give rise to muscle and dermis (Ben-Yair and Kalcheim, 2005; Lepper and Fan, 2010). Dermal stem/progenitors later downregulate Pax7 expression, in contrast to myogenic stem/progenitors, which maintain high levels of Pax7 during embryonic, foetal and postnatal myogenesis. This marker is then downregulated during myoblast differentiation (Tajbakhsh, 2009; Murphy and Kardon, 2011). Notably, embryonic [embryonic day (E) 9-14.5] and foetal (E14.5-18.5) myoblasts and differentiated cells are molecularly and phenotypically distinct (Cusella-De Angelis et al., 1994; Biressi et al., 2007a; Tajbakhsh, 2009). Embryonic myoblasts in the mouse fuse to form primary fibres from E11 and they establish the basic muscle pattern. Foetal myoblasts appear from E14.5 and subsequently form larger secondary fibres, and, unlike their embryonic counterparts, their differentiation is blocked by Tgf and -catenin (Cusella-De Angelis et al., 1994; Hutcheson et al., 2009). Juvenile satellite cells are then observed under the myofibre basement membrane from E16.5 and they act as reservoirs of quiescent adult muscle stem (satellite) cells from 3 weeks postnatally. Although it is thought that a continuum of stem cells that resists differentiation assures these waves of distinct myogenic populations (Gros et al., 2005; Kassar-Duchossoy et al., 2005; Relaix et al., 2005; Tajbakhsh, 2009; Murphy and Kardon, 2011) and that distinct transcriptome dynamics defines their progeny (Biressi et al., 2007b), little, if any, information is available on how these processes are regulated within muscle stem/progenitor cells. The identification of the transcription factor Nfix, which regulates Stem Cells and Development, Department of Developmental Biology, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, 75105 Paris, France.