39 The Myogenic Helix-Loop-Helix Family: Regulators of Skeletal Muscle Determination and Differentiation

OVERVIEW Pivotal in the control of skeletal muscle determination and differentiation are a family of regulatory proteins that can activate the myogenic differentiation program when expressed in a variety of cell types. Induction of both muscle-specific structural genes and other muscle-specific regulators in various cellular backgrounds indicates that the myogenic helix-loop-helix (HLH) genes are nodal points of regulation controlling muscle gene expression. This family of proteins has been evolutionarily conserved, and homologous proteins have been implicated in controlling skeletal muscle gene expression in nematodes, insects, amphibians, birds, and mammals. These proteins share a region of structural homology (basic helix-loop-helix motif) that serves as a DNA binding–protein oligomerization structure. In this chapter, we discuss the structure, function, and regulation of the myogenic HLH proteins and how interactions between these factors and other non-tissue-restricted HLH proteins control muscle gene expression. INTRODUCTION A key aspect of development is the specification of cell fate during embryogenesis. The phenotypic manifestation of cell fate (differentiation) is usually uncoupled, both temporally and spatially, from the initial cellular determination events. Therefore, in the absence of biochemical markers, cell determination is functionally defined as the latent capacity of a cell or its progeny to elaborate a specific differentiation repertoire in a permissive environment. During the past several years, both genetic and biochemical approaches have shed considerable light on a family of factors that apparently control skeletal muscle cell determination and differentiation in both vertebrates and invertebrates. The skeletal muscle lineage has been particularly amenable to analysis, due primarily...