Regulation of paraxial mesoderm patterning

Harvard University (Medical School), Boston MA

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Abstract

DESCRIPTION (provided by applicant): The broad aim of this project is to elucidate the regulatory circuits that pattern paraxial mesodermal cell fates in both the somites and in the cranial paraxial mesoderm. Prior studies have indicated that Shh and Wnt signals from the axial tissues and from the surface ectoderm, work in combination with BMP signals from the lateral plate mesoderm to pattern different cell types in the somites. Signals that induce dermomyotomal and myotomal gene expression simultaneously repress the expression of sclerotomal markers. Conversely, signals that induce sclerotomal gene expression simultaneously repress the expression of dermomyotomal/myotomal markers. In contrast to somitic myogenesis, the source of signals that induce skeletal muscle formation in the head remains obscure. While Wnt and Hedgehog signals induce myogenesis in somites these signals have the opposite effect on head mesoderm, where they block the formation of skeletal muscle. Whereas trunk myogenesis is induced by signals from the axial tissues, head myogenesis is blocked by cues from the dorsal neural tube. We have found that the timing and kinetics of head myogenesis are correlated with an inductive signal(s) secreted by the cranial neural crest (CNC), that both isolated CNC cells or medium conditioned by such cells can directly induce skeletal myogenesis in head mesoderm, and that BMP-antagonists expressed in the cranial neural crest can mimic the muscle inducing activity of this tissue. In this proposal I outline the following specific aims. (1). Determine if Pax-3, and its related gene Pax-7, are necessary and sufficient to both induce dorsal somitic cell fates and block the induction of sclerotomal gene expression in the dorsal regions of the somite. (2) Determine if Nkx3.2, Nkx3.1 and Sox-9 are necessary and sufficient to induce both ventral somitic cell fates and block the induction of dermomyotomal/myotomal gene expression in the ventral regions of the somite. (3) Determine if dermomyotomal gene expression requires both Wnt and notch signals. (4) Determine if signals from the cranial neural crest are necessary for the formation of cranial muscle, and determine how Wnt signals block the formation of head muscle.