Individual Limb Muscle Bundles Are Formed through Progressive Steps Orchestrated by Adjacent Connective Tissue Cells during Primary Myogenesis

Abstract

Summary: Although the factors regulating muscle cell differentiation are well described, we know very little about how differentiating muscle fibers are organized into individual muscle tissue bundles. Disruption of these processes leads to muscle hypoplasia or dysplasia, and replicating these events is vital in tissue engineering approaches. We describe the progressive cellular events that orchestrate the formation of individual limb muscle bundles and directly demonstrate the role of the connective tissue cells that surround muscle precursors in controlling these events. We show how disruption of gene activity within or genetic ablation of connective tissue cells impacts muscle precursors causing disruption of muscle bundle formation and subsequent muscle dysplasia and hypoplasia. We identify several markers of the populations of connective tissue cells that surround muscle precursors and provide a model for how matrix-modifying proteoglycans secreted by these cells may influence muscle bundle formation by effects on the local extracellular matrix (ECM) environment. : Besse et al. describe how differentiating muscle fibers are transformed into limb muscle bundles. Using gene deletion and genetic ablation, they demonstrate the importance of surrounding connective tissue cells in orchestrating muscle morphogenesis, identify markers of this population in limbs, and provide a model for how these cells influence muscle precursors. Keywords: muscle, tissue morphogenesis, irregular connective tissue, muscle connective tissue, Tbx5, Holt-Oram syndrome, HOS