Recent studies have postulated that distinct regulatory cascades control myogenic differentiation in the head and the trunk. However, although the tissues and signaling molecules that induce skeletal myogenesis in the trunk have been identified, the source of the signals that trigger skeletal muscle formation in the head remain obscure. Here we show that although myogenesis in the trunk paraxial mesoderm is induced by Wnt signals from the dorsal neural tube, myogenesis in the cranial paraxial mesoderm is blocked by these same signals. In addition, BMP family members that are expressed in both the dorsal neural tube and surface ectoderm are also potent inhibitors of myogenesis in the cranial paraxial mesoderm. We provide evidence suggesting that skeletal myogenesis in the head is induced by the BMP inhibitors, Noggin and Gremlin, and the Wnt inhibitor, Frzb. These molecules are secreted by both cranial neural crest cells and by other tissues surrounding the cranial muscle anlagen. Our findings demonstrate that head muscle formation is locally repressed by Wnt and BMP signals and induced by antagonists of these signaling pathways secreted by adjacent tissues. Vertebrate locomotion crucially depends on trunk skeletal muscles, which all derive from the segmented paraxial mesoderm termed somites (for review, see Christ and Ordahl 1995). During the past decade, the tissues and signaling molecules that induce the formation of skeletal muscle from somites have been intensively studied. These studies have indicated that somitic myogenesis in the trunk is affected by signals emanating from the axial tissues, the surface ectoderm, and the lateral plate mesoderm. Wnt family members expressed in the dorsal neural tube work together with Sonic hedgehog (Shh) expressed in the notochord to activate myogenic bHLH gene expression (that is, Myf-5 and MyoD) in the epaxial component of the myotome (Munsterberg et al. 1995;Stern et al. 1995;Tajbakhsh et al. 1998;Borycki et al. 2000;Gustafsson et al. 2002). In addition, Wnt signals from the dorsal ectoderm have been demonstrated to up-regulate the expression of MyoD in the hypaxial component of the myotome (Tajbakhsh et al. 1998). Furthermore, BMP signals from the lateral plate have been shown to delay the activation of myogenic bHLH gene expression in the hypaxial muscle progenitors relative to those that form the epaxial musculature (Pourquié et al. 1996). In contrast to our understanding of how skeletal muscle is induced in the trunk, the tissues and signaling pathways that induce the formation of skeletal muscle in the head have not yet been elucidated.In the vertebrate head, ∼40 skeletal muscles are present, which, instead of serving for locomotion, rather move the eye, control the cranial openings, or facilitate food uptake and, in humans, speech (for review, see Wachtler and Jacob 1986). Although the hypobranchial muscles, the tongue muscles, and the muscles of the posterior branchial arches (BAs), develop from the somites, the remainder of the head muscles (that is, the "genui...

Activated by dorsalizing and lateralizing signals, the Pax3 gene is an early marker for the entire paraxial mesoderm and its dorsal derivative, the dermomyotome. Later, its expression becomes restricted to the lateral dermomyotome and to the migratory muscle precursors giving rise to the hypaxial musculature. To understand better the role that Pax3 plays during development of paraxial mesoderm-derived structures, we followed the development of the musculature and skeleton in the murine Pax3 mutant Splotch. We found that the mutant dermomyotomes and myotomes failed to organize and to elongate medially and laterally, leading to the reduction and malformation of the entire trunk musculature. Mutants lacked ventral aspects of the body wall musculature and muscles derived from migratory myoblasts, suggesting a crucial function for Pax3 in the long-range migration of muscle precursors giving rise to the ventral hypaxial musculature. In addition, severe malformations were detected in the skeleton. The axial and appendicular skeleton displayed malformations and in particular multiple bone fusions.

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The head mesoderm is the mesodermal tissue on either side of the brain, from forebrain to hindbrain levels, and gives rise to the genuine head muscles. Its relatedness to the more posterior paraxial mesoderm, the somites, which generate the muscles of the trunk, is conversely debated. To gain insight into the molecular setup of the head mesoderm, its similarity or dissimilarity to the somitic mesoderm, and the implications of its setup for the progress of muscle formation, we investigated the expression of markers (1) for mesoderm segmentation and boundary formation, (2) for regional specification and somitogenesis and (3) for the positive and negative control of myogenic differentiation. We show that the head mesoderm is molecularly distinct from somites. It is not segmented; even the boundary to the first somite is ill-defined. Importantly, the head mesoderm lacks the transcription factors driving muscle differentiation while genes suppressing differentiation and promoting cell proliferation are expressed. These factors show anteroposteriorly and dorsoventrally regionalised but overlapping expression. Notably, expression extends into the areas that actively contribute to the heart, overlapping with the expression of cardiac markers.