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The mechanisms of Hedgehog signalling and its roles in development and disease

Key Points

  • The Hedgehog signalling pathway has diverse functions in animal development and tissue homeostasis. Dysregulation of the pathway has been implicated in several developmental syndromes and cancers.

  • The production of Hedgehog (HH) ligands involves autoproteolytic cleavage and the addition of lipid moieties such as cholesterol and palmitic acid. Several dedicated proteins are required for the secretion of the ligand.

  • Novel mechanisms involving ligand multimerization, complex formation with additional soluble proteins and association with components of the extracellular matrix, such as the heparan sulphate proteoglycans, have been proposed to explain the dispersion of lipidated HH proteins through tissues.

  • Signal transduction requires a number of transmembrane proteins, most notably Patched 1 (PTC) and Smoothened (SMO). The mechanism by which the signal is transduced from PTC to SMO is unclear. Strikingly, in vertebrates, but not Drosophila melanogaster, signal transduction requires the primary cilia of cells, identifying a function for this previously enigmatic organelle.

  • Intracellularly, signalling involves Suppressor of Fu (SUFU), the kinesin proteins Costal 2 (Cos2) in D. melanogaster and KIF7 in vertebrates and several kinases. Signalling culminates with the regulation of the D. melanogaster Cubitus interruptus (Ci) and vertebrate GLI families of transcription factors. HH signalling converts the Ci and GLI proteins from transcriptional repressors to activators by inhibiting their proteolytic cleavage.

  • The various functions of HH signalling have predominately been ascribed to its regulation of gene expression, and the relevant transcriptional networks are beginning to be dissected. Recently, however, non-canonical branches to the signalling pathway have been found, and these might contribute to some HH functions.

  • HH signalling regulates the survival and proliferation of tissue progenitor and stem populations. This function is linked to its role in tumour formation. Several small-molecule antagonists and agonists that target SMO have been identified, and these show promise in the treatment of HH-related pathologies. In 2012, the approval of the Food and Drug Administration (FDA) was obtained for the first drug that targets HH signalling in the skin cancer basal cell carcinoma.

Abstract

The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.

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Figure 1: Hedgehog protein biogenesis and release.
Figure 2: Reception of Hedgehog and initiation of signal transduction.
Figure 3: Schematic of Ci and GLI regulation.

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Acknowledgements

The authors apologize to their colleagues whose work has gone unmentioned owing to space limitations. J.B is supported by the Medical Research Council (MRC, UK) and the Wellcome Trust, and P.P.T. by the Ligue National Contre le Cancer Program 'Equipe labellisée 2012'.

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Correspondence to James Briscoe or Pascal P. Thérond.

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Briscoe, J., Thérond, P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14, 416–429 (2013). https://doi.org/10.1038/nrm3598

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