Members of the Twist-family of bHLH proteins play a pivotal role in a number of essential developmental programs. Twist-family bHLH proteins function by dimerizing with other bHLH members and binding to cis-regulatory elements, called E-boxes. While Twist-family members may simply exhibit a preference in terms of high-affinity binding partners, a complex, multilevel cascade of regulation creates a dynamic role for these bHLH proteins. We summarize in this review information on each Twist-family member concerning expression pattern, function, regulation, downstream targets, and interactions with other bHLH proteins. Additionally, we focus on the phospho-regulatory mechanisms that tightly control posttranslational modification of Twist-family member bHLH proteins. Twist1, Twist2, Hand1, Hand2, Paraxis, Scleraxis, limb, heart, trophoblast, phosphoregulation, dimerization The Twist-family of basic helix-loop-helix (bHLH) factors is an evolutionarily conserved family of proteins that play diverse roles in both embryonic development and pathological disease. These diverse roles are reflected in the functional mechanisms that govern Twist-family biological activity. The requirement of bHLH factors to form a dimer complex is well established and recently a number of groups have shown that Twist family proteins have broad sets of potential dimer partners. In addition to Class A bHLH factors (E-proteins), homodimerization and heterodimerization between Twist-family members form important and functional dimer complexes that are required for proper development. Given the broad partially overlapping expression patterns of Twist factors observed within the developing embryo and the potential of these factors to form numerous unique transcriptional complexes, the spatio-temporal transcriptional regulation of Twistfamily members is a key component of the functional regulation defining specification and differentiation. Additionally, phosphorylation of conserved threonine and serine residues within the first amphipathic α-helix of Twist-family proteins exerts a second level of control, effecting protein dimer affinities with potential partners as well as dictating DNA-binding affinities in a cis-element dependent manner. Moreover, phosphoregulation can regulate protein localization within the cell thereby positioning the Twist protein (and perhaps its partner) in a functional or non-functional environment. Given the recent new insights into the developmental and Int. J. Dev. Biol. 53: 909-924 (2009)
KEY WORDS: