Further Development 17.6: An Emerging Model of Neural Crest-Regulated Myogenesis

Paraxial Mesoderm: The Somites and Their Derivatives

Both the dorsomedial and ventrolateral lips (DML and VLL) of the dermomyotome are considered to function as self-perpetuating “cellular growth engines” capable of self-renewal and of creating differentiating myocytes (Denetclaw and Ordahl 2000; Ordahl et al. 2001). What regulates which cells within the DML will adopt a renewal fate and which will mature into muscle? We have described an array of paracrine factors from the neural tube, surface ectoderm, and notochord that influence myogenesis; however, matriculation of cells into muscle development from the DML appears to occur in a highly mosaic and random fashion (Hirst and Marcelle 2015). Although transient, another potential source of signals could be the migrating population of neural crest cells that passes directly adjacent to the DML (see also Chapter 15).

In agreement with the mosaic maturation of muscle from the DML is the correlation that the Notch signaling pathway is activated in muscle progenitors. Within the tip of the DML, some cells begin to express Notch-1, Hes1, and Lunatic fringe (among others), and these cells develop into myofibers of the myotome. Christophe Marcelle’s research group has shown that a sporadic portion of migrating neural crest cells expresses Delta1 and comes in direct contact with the Notch-containing membranes at the DML (often through outstretched filopodia) (Figure 1A, B). Removal of neural crest cells or loss of Delta1 function in the neural crest greatly reduces the myotome, whereas increased expression of Delta1 only in the neural crest is sufficient to induce greater Myf5 expression in the dermomyotome and expanded myogenesis (Rios et al. 2011).

Rios and colleagues (2011) have named this neural-crest-transported mode of signaling “kiss and run” because it may represent a more widespread mechanism of signal dispersal. In fact, ventrally migrating neural crest cells also carry Wnt1 (Figure 1C), the same protein we previously described as being important in myogenesis and supplied by the dorsal neural tube. These neural crest cells require the GPC4 heparan sulfate proteoglycan to bind Wnt1 and present it to the DML as they pass by, which consequently establishes a gradient of Wnt1 protein based on the rate of migration (Figure 1D). Neural crest-derived Wnt1 is required for the upregulation of Wnt11 in the dermomyotome and the proper organization of the myotome (Serralbo and Marcelle 2014). Finally, as neural crest cells migrate through the sclerotome, they secrete neuregulin-1, a paracrine factor that prevents the premature differentiation of myoblasts into muscle cells, which helps maintain the pool of myogenic progenitors (Ho et al. 2011). Thus, like a bee unknowingly carrying pollen to flowers along its journey, a neural crest cell delivers morphogenetic signals to cells throughout the somite that influence their differentiation and growth.

**Figure 1** Neural crest cells carry a message of myotome maturation. (A) HNK1-positive neural crest cells (red) express *Delta1* (blue). NT, neural tube; DML, dorsomedial lip; TZ, transition zone; MY, maturing myotome. (B) Cells of the dorsomedial lip and maturing myotome express the downstream target gene for Notch, *Hes1* (blue). (C) Double fluorescent analysis shows that neural crest cells in fact express Wnt1 (arrows show two examples of co-localized Wnt1 in neural crest cells). Only a portion of the chick trunk is shown in these cross sections. S, somite. (D) Model of the transient interactions between neural crest cells and the DML myogenic precursors through Notch-Delta and Wnt signaling. DML cells extend long filopodia into the periphery of the dermomyotome through the path of migrating neural crest cells. Different neural crest cells are illustrated with different colors to distinguish Delta-expressing (red) from Wnt1-expressing (blue) neural crest cells. In addition, neural crest cells also secrete neuregulin-1 (gold), which prevents precocious differentiation of myoblast (green cells) from DML progenitors (purple cells).

Literature Cited

Hirst, C. E. and C. Marcelle. 2015. The avian embryo as a model system for skeletal myogenesis. Results Probl. Cell Differ. 56: 99–122.
PubMed Link

Ho, A. T. V., S. Hayashi, D. Bröhl, F. Auradé, R. Rattenbach and F. Relaix. 2011. Neural crest cell lineage restricts skeletal muscle progenitor cell differentiation through Neuregulin1-ErbB3 signaling. Dev. Cell 21: 273–287.
PubMed Link

Denetclaw, W. F. and C. P. Ordahl. 2000. The growth of the dermomyotome and formation of early myotome lineages in thoracolumbar somites of chicken embryos. Development 127: 893–905.
PubMed Link

Ordahl, C. P., E. Berdougo, S. J. Venters, and W. F. J. Denetclaw. 2001. The dermomyotome dorsomedial lip drives growth and morphogenesis of both the primary myotome and dermomyotome epithelium. Development 128: 1731–1744.
PubMed Link

Rios, A. C., O. Serralbo, D. Salgado, and C. Marcelle. 2011. Neural crest regulates myogenesis through the transient activation of Notch. Nature 473: 532–535.
PubMed Link

Serralbo, O. and C. Marcelle. 2014. Migrating cells mediate long-range WNT signaling. Development. 141: 2057–2063.
PubMed Link

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