Hedgehog signaling in animal development: paradigms and principles

Hedgehog signaling in animal development: paradigms and principles

2001 | Philip W. Ingham and Andrew P. McMahon
Hedgehog signaling plays a crucial role in embryonic development, regulating growth, patterning, and morphogenesis in vertebrates and insects. This review discusses the key functions of Hedgehog (Hh) proteins, their signaling mechanisms, and their conservation across species. The discovery of Hh genes was initially made in Drosophila by Nüsslein-Volhard and Wieschaus, who identified mutations affecting segment polarity. The cloning of Hh and its role in segment-polarity genes led to the identification of the Hh family, which includes several related genes in vertebrates, such as Desert hedgehog (Dhh), Indian hedgehog (Ihh), and Sonic hedgehog (Shh). Shh is particularly important in vertebrate development, acting as a morphogen in the neural tube and limb, and is involved in various developmental processes, including germ-cell migration and optic lamina development. Hh signaling is mediated through a complex network of interactions, including the receptor Patched (Ptc) and the G-protein-coupled receptor Smoothened (Smo). Ptc inhibits Smo activity, but Hh binding to Ptc relieves this inhibition, allowing Smo to activate its intracellular targets. The signaling process involves the internalization of the Hh-Ptc complex, which is then targeted to lysosomes. The activity of Smo is essential for all aspects of Hh signaling, and its function is regulated by various mechanisms, including membrane trafficking and interactions with other proteins. Hh signaling is also involved in long-range patterning in the vertebrate neural tube and limb. In the neural tube, Shh is produced by the notochord and floor plate, and its activity is crucial for specifying ventral cell identities. In the limb, Shh is produced by the zone of polarizing activity (ZPA) and is essential for determining the antero-posterior polarity of the limb. The concentration of Shh determines the pattern of cell fates, and its signaling is regulated by various factors, including the receptor Ptc and the G-protein-coupled receptor Smo. The biosynthesis and structure of Hh proteins involve intramolecular cleavage and lipid modifications, such as cholesterol coupling and palmitoylation, which are essential for their function. These modifications help in the retention of Hh proteins in the membrane and facilitate their signaling. The study of Hh signaling has provided insights into the mechanisms of cell-cell communication and the regulation of developmental processes. Misregulation of Hh signaling has been linked to various pathologies, including cancers such as basal cell carcinoma. Overall, Hh signaling is a fundamental aspect of embryonic development, with conserved mechanisms across species, highlighting its importance in the regulation of body plan formation.Hedgehog signaling plays a crucial role in embryonic development, regulating growth, patterning, and morphogenesis in vertebrates and insects. This review discusses the key functions of Hedgehog (Hh) proteins, their signaling mechanisms, and their conservation across species. The discovery of Hh genes was initially made in Drosophila by Nüsslein-Volhard and Wieschaus, who identified mutations affecting segment polarity. The cloning of Hh and its role in segment-polarity genes led to the identification of the Hh family, which includes several related genes in vertebrates, such as Desert hedgehog (Dhh), Indian hedgehog (Ihh), and Sonic hedgehog (Shh). Shh is particularly important in vertebrate development, acting as a morphogen in the neural tube and limb, and is involved in various developmental processes, including germ-cell migration and optic lamina development. Hh signaling is mediated through a complex network of interactions, including the receptor Patched (Ptc) and the G-protein-coupled receptor Smoothened (Smo). Ptc inhibits Smo activity, but Hh binding to Ptc relieves this inhibition, allowing Smo to activate its intracellular targets. The signaling process involves the internalization of the Hh-Ptc complex, which is then targeted to lysosomes. The activity of Smo is essential for all aspects of Hh signaling, and its function is regulated by various mechanisms, including membrane trafficking and interactions with other proteins. Hh signaling is also involved in long-range patterning in the vertebrate neural tube and limb. In the neural tube, Shh is produced by the notochord and floor plate, and its activity is crucial for specifying ventral cell identities. In the limb, Shh is produced by the zone of polarizing activity (ZPA) and is essential for determining the antero-posterior polarity of the limb. The concentration of Shh determines the pattern of cell fates, and its signaling is regulated by various factors, including the receptor Ptc and the G-protein-coupled receptor Smo. The biosynthesis and structure of Hh proteins involve intramolecular cleavage and lipid modifications, such as cholesterol coupling and palmitoylation, which are essential for their function. These modifications help in the retention of Hh proteins in the membrane and facilitate their signaling. The study of Hh signaling has provided insights into the mechanisms of cell-cell communication and the regulation of developmental processes. Misregulation of Hh signaling has been linked to various pathologies, including cancers such as basal cell carcinoma. Overall, Hh signaling is a fundamental aspect of embryonic development, with conserved mechanisms across species, highlighting its importance in the regulation of body plan formation.
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