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Regulation of Trunk Myogenesis by the Neural Crest: A New Facet of Neural Crest-Somite Interactions

2011; Elsevier BV; Volume: 21; Issue: 2 Linguagem: Inglês

10.1016/j.devcel.2011.07.009

1878-1551

Chaya Kalcheim,

Hedgehog Signaling Pathway Studies

It is well established that the somitic mesoderm regulates early stages of neural crest development and further segmentation of crest-derived peripheral ganglia. The possibility that neural crest progenitors feed back on the somites was, however, not explored. Two recent studies provide evidence that the neural crest regulates somite-derived myogenesis by distinct mechanisms. It is well established that the somitic mesoderm regulates early stages of neural crest development and further segmentation of crest-derived peripheral ganglia. The possibility that neural crest progenitors feed back on the somites was, however, not explored. Two recent studies provide evidence that the neural crest regulates somite-derived myogenesis by distinct mechanisms. Prospective neural crest cells (NCCs) transiently reside in the dorsal neural tube (NT) as epithelial progenitors and then exit the NT following an epithelial-to-mesenchymal conversion. In the trunk, NCCs generate sympathetic ganglia, Schwann cells, dorsal root sensory ganglia, and melanocytes. Following emigration and during migration, NCCs interact with the paraxial mesoderm. They migrate between adjacent somites, between somites and NT, ventral to the dermomyotome (DM), and through the sclerotome. Migration through the last three pathways is confined to the rostral domain of each segment, prefiguring the metameric organization of the peripheral nervous system (Gammill and Roffers-Agarwal, 2010Gammill L.S. Roffers-Agarwal J. Dev. Biol. 2010; 344: 555-565Crossref PubMed Scopus (59) Google Scholar, Le Douarin and Kalcheim, 1999Le Douarin N.M. Kalcheim C. The Neural Crest.Second Edition. Cambridge University Press, New York1999Crossref Google Scholar). Extensive evidence documents that these encounters between NCCs and somites play a pivotal role in the development of both partners. For instance, the dorsal NT patterns the somite-derived DM, influencing myogenesis (Figure 1A ) and subsequent formation of the dorsal dermis (Marcelle et al., 1997Marcelle C. Stark M.R. Bronner-Fraser M. Development. 1997; 124: 3955-3963Crossref PubMed Google Scholar, Sela-Donenfeld and Kalcheim, 2002Sela-Donenfeld D. Kalcheim C. Dev. Biol. 2002; 246: 311-328Crossref PubMed Scopus (66) Google Scholar, and references therein). Reciprocally, the medial lip of the DM inhibits transcription of noggin in the NT, which relieves repression of BMP signaling activity, stimulating emigration of NCCs (Figure 1B). Thus, the timing of NCC delamination is regulated by developing somites that serve as substrates for their subsequent migration (Sela-Donenfeld and Kalcheim, 2000Sela-Donenfeld D. Kalcheim C. Development. 2000; 127: 4845-4854PubMed Google Scholar). In spite of these multiple interactions, the notion that NCCs signal the adjacent somites during migration in the trunk was not explored before. In the head, NCCs pattern the cranial mesoderm and, more specifically, affect migration and differentiation of craniofacial muscles (Rinon et al., 2007Rinon A. Lazar S. Marshall H. Büchmann-Møller S. Neufeld A. Elhanany-Tamir H. Taketo M.M. Sommer L. Krumlauf R. Tzahor E. Development. 2007; 134: 3065-3075Crossref PubMed Scopus (132) Google Scholar and references therein). Two recent studies by Rios et al. and Ho et al. show that trunk NCCs also affect development of the somite-derived DM to regulate the balance between Pax7-positive progenitors and differentiating muscle. Common to both studies is the finding that depletion of migrating NCCs compromised myogenesis. The Marcelle group (Rios et al., 2011Rios A.C. Serralbo O. Salgado D. Marcelle C. Nature. 2011; 473: 532-535Crossref PubMed Scopus (116) Google Scholar) ablated NCCs by electroporating chick embryos with a DNA construct encoding diphteria toxin under the regulation of the NCC-specific Sox10 promoter; the Relaix group (Ho et al., 2011Ho A.H.T.V. Hayashi S. Brohl D. Aurade F. Rattenbach R. Relaix F. Dev. Cell. 2011; 21 (this issue): 273-287Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) analyzed Sox10-deficient mouse embryos. Each study then diverged to use a variety of other methods to address distinct stages and domains of the prospective myotome. Rios et al. focused on early myogenesis derived from the dorsomedial lip of the DM, while Ho et al. addressed the central and hypaxial domains of the DM and of the myotome itself. In their work, the Marcelle team reports the intriguing finding that progenitors of the medial DM lip that activate Notch signaling translocate into the myotome and transit from a Pax7-positive to a Myf5-positive state, followed by differentiation into myocytes (Figure 1C). They further report that this Notch activation is driven by "en passant" NCCs that express the Delta1 ligand. Their most prominent finding is that in order to trigger myogenesis at the expense of maintenance of the progenitor state, Notch activation should be transient, as constitutive activation of this pathway led progenitors to leave the medial lip, yet they maintained Pax7 and failed to differentiate. It would be relevant to examine whether other streams of migratory NCCs also express Notch ligands, and if so, whether this transient signaling affects additional regions of the DM. Furthermore, it would be interesting to determine whether transient Notch activation mediates NCC-DM interactions also in other species. This is particularly important because Notch activity is generally associated with maintenance of the progenitor state at the expense of terminal differentiation, in both embryonic and adult murine muscles, and partial loss of Delta activity results in muscle enlargement (see, for example, Schuster-Gossler et al., 2007Schuster-Gossler K. Cordes R. Gossler A. Proc. Natl. Acad. Sci. USA. 2007; 104: 537-542Crossref PubMed Scopus (195) Google Scholar and Vasyutina et al., 2007Vasyutina E. Lenhard D.C. Birchmeier C. Cell Cycle. 2007; 6: 1451-1454Crossref PubMed Scopus (1) Google Scholar). Genetic studies in the mouse performed by the Relaix team (Ho et al., 2011Ho A.H.T.V. Hayashi S. Brohl D. Aurade F. Rattenbach R. Relaix F. Dev. Cell. 2011; 21 (this issue): 273-287Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) highlighted the significance of NCC-derived Neuregulin1 that, acting primarily through the ErbB3 receptor, regulates muscle development by maintaining the Pax7 progenitor pool, thereby preventing premature myogenic differentiation (Figure 1C). To specifically attenuate certain aspects of NCC identity and function, they expressed a dominant-negative Pax3 transcription factor using an NC-specific Wnt1-Cre driver. This allowed direct targeting of dominant-negative Pax3 in trunk NCCs without affecting other Pax3-expressing lineages, such as the somites themselves. Under these conditions, the authors monitored a 30% reduction in NCCs in ventral domains, a corresponding partial loss of Pax7-positive muscle progenitors in both the central DM and the hypaxial muscle, and an increase in the expression of early markers of the myogenic program, such as MyoD. The authors concluded that NCC defects caused an exhaustion of the Pax7+ progenitor pool, finally leading to smaller muscles. The authors went on to characterize Neuregulin1 as a ligand expressed by NCCs that partially accounts for these effects: specific ablation of Neuregulin1 in NCCs results in somites with reduced size, depletion of Pax7-positive progenitors, and a concomitant upregulation of MyoD. This is particularly interesting because the conditional Neuregulin1 mutants had apparently normal NCCs, uncoupling the development of the NC from actual NCC-derived signaling. Furthermore, knocking down the Neuregulin receptor ErbB3, in somite explants, recapitulated a similar myogenic defect. In the future, it would be valuable to better characterize in the mouse whether progenitors in the different domains of the DM respond similarly and compare their responsiveness with that of Pax7-expressing precursors that already colonized the myotome. Taken together, these results show that migrating trunk NCCs regulate myogenesis. This is likely part of a mechanism aimed at coordinating the development of two tightly interacting systems, the peripheral nervous system and that of muscle. On the one hand, NCCs provide promyogenic cues (transient Delta1/Notch activation), and on the other, they act on progenitor maintenance (via Neuregulin/ErbB). It will be important to further elaborate on this concept by identifying additional NCC-derived signals in several species, defining the precise myogenic progenitors they affect, examining the nature of their activities on the balance between progenitors and differentiated cells, and analyzing whether all NCCs express the same battery of genes that affect myogenesis, or alternatively, whether NC-somite signaling is compartmentalized in space and time to distinct NC subsets. Neural Crest Cell Lineage Restricts Skeletal Muscle Progenitor Cell Differentiation through Neuregulin1-ErbB3 SignalingHo et al.Developmental CellJuly 21, 2011In BriefCoordinating the balance between progenitor self-renewal and myogenic differentiation is required for a regulated expansion of the developing muscles. Previous observation that neural crest cells (NCCs) migrate throughout the somite regions, where trunk skeletal muscles first emerge, suggests a potential role for these cells in influencing early muscle formation. However, specific signaling interactions between NCCs and skeletal muscle cells remain unknown. Here we show that mice with specific NCC and peripheral nervous system defects display impaired survival of skeletal muscle and show skeletal muscle progenitor cell (MPC) depletion due to precocious commitment to differentiation. Full-Text PDF Open Archive