EGFR/ErbB SIGNALING IN LIMB PATTERNING

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The goal of this project is to explore the roles of ErbB signaling in limb patterning. The ErbB family consists of ErbB1 (also known as epidermal growth factor receptor or EGFR); three other receptors (ErbB2-4); and 11 ligands. The ErbB signaling network is considered a paradigm for diversification of cell signal responses, as distinct signals are generated by formation of ErbB heterodimers and activation by multiple ligands. Moreover, the ErbB signaling network plays an important role as a central convergence point for multiple signaling pathways, integrating signals emanating from other receptor classes. ErbB1, ErbB4 and the ligands EGF, TGF-alpha and Nrg1 are expressed in chick limbs in fashions consistent with patterning roles. We have found that expression of activated ErbB1 causes limb defects including mirror-image polydactyly, ectopic AERs, duplicated dorsal structures and syndactyly, suggesting ErbB1 may be involved in AP and DV patterning, AER formation, and interdigital regression. We have also found that expression of a dominant negative ErbB, which inhibits signals from multiple ErbBs including ErbB4 but not ErbB1, causes limb defects including loss of distal structures, indicating that an endogenous ErbB other than ErbB1 is important for limb patterning. We will employ multiple gain and loss of function approaches to investigate the roles of ErbB1, ErbB4 and their ligands in mediating limb patterning events, using in chick limbs retroviral vectors, and in mouse limbs, limb tissue-specific promoters. We will explore the activation of intracellular signaling cascades, formation of ErbB heterodimers, and regulatory relationships with other limb patterning signals such as Shh, FGF, Wnt, BMP, and IGF. Since ErbB2 and ErbBS are also expressed in the limb, to gain insight into roles for other ErbBs, and to address potential functional redundancy among ErbB members, we will inhibit multiple ErbBs simultaneously in the limb. These studies should provide insight into the previously unappreciated role of the ErbB signaling network as a key regulator of limb morphogenesis.