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Cellular and molecular mechanisms of Hedgehog signalling

Nature Reviews Molecular Cell Biology volume 24, pages 668–687 (2023)Cite this article

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Abstract

The Hedgehog signalling pathway has crucial roles in embryonic tissue patterning, postembryonic tissue regeneration, and cancer, yet aspects of Hedgehog signal transmission and reception have until recently remained unclear. Biochemical and structural studies surprisingly reveal a central role for lipids in Hedgehog signalling. The signal — Hedgehog protein — is modified by cholesterol and palmitate during its biogenesis, thereby necessitating specialized proteins such as the transporter Dispatched and several lipid-binding carriers for cellular export and receptor engagement. Additional lipid transactions mediate response to the Hedgehog signal, including sterol activation of the transducer Smoothened. Access of sterols to Smoothened is regulated by the apparent sterol transporter and Hedgehog receptor Patched, whose activity is blocked by Hedgehog binding. Alongside these lipid-centric mechanisms and their relevance to pharmacological pathway modulation, we discuss emerging roles of Hedgehog pathway activity in stem cells or their cellular niches, with translational implications for regeneration and restoration of injured or diseased tissues.

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Fig. 1: Overview of mammalian Hedgehog signalling.
Fig. 2: Lipid modification of Hedgehog.
Fig. 3: The ligand-binding pockets of Smoothened.
Fig. 4: Sterol transport by Patched.
Fig. 5: Dispatched release of Hedgehog from the cell membrane is driven by Na+ flux.
Fig. 6: Model of Hedgehog signal transduction at the cell surface.
Fig. 7: Hedgehog signalling has context-dependent roles in tissues.

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Acknowledgements

The authors thank W. Kong for advice and K. Ding for assistance with Fig. 5. Work in P.A.B.’s laboratory is supported by NIH grant R01GM102498, the Department of Urology of Stanford University School of Medicine and the Ludwig Cancer Institute. Y.Z. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2405-20). This article is dedicated to the memory of Dr. Jynho Kim (1964–2016).

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  1. Yunxiao Zhang

    Present address: Howard Hughes Medical Institute and Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA

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  1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Yunxiao Zhang & Philip A. Beachy

  2. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA

    Philip A. Beachy

  3. Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA

    Philip A. Beachy

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Glossary

Alanine scanning

An experimental approach in which each amino acid within a domain of interest of a studied protein is replaced by alanine and the protein’s function is tested.

Cyclopia

The development of a single eye in the midline of the face — an extreme form of a congenital malformation known as holoprosencephaly. Cyclopia and holoprosencephaly are associated with loss of Hedgehog signalling and can be caused in grazing animals by ingestion of Veratrum californicum (corn lily), which contains the Hedgehog pathway inhibitor cyclopamine.

Cytonemes

Specialized projections from cell bodies that may function in long-range delivery of responses to signalling molecules.

Glypicans

A family of heparan sulfate proteoglycans anchored to the cell surface through a glycosylphosphatidylinositol related to Dally and Dally-like (Dlp) proteins in fruitflies. These heparan sulfate proteoglycans interact with and can affect cellular responses to signalling molecules, including Hedgehog.

Morphogen

An extracellular signal produced at a particular location within a developing embryo that specifies the pattern of differentiation and proliferation in surrounding cells. The Hedgehog protein signal acts as a morphogen in developing tissues of many multicellular animals.

Organizers

A group of morphogen-producing cells that specifies the pattern of cell differentiation within adjacent structures during embryonic development. Graded Hedgehog signalling is responsible for the activity of well-studied organizers such as the notochord in its patterning of the neural tube and of the somites, and the zone of polarizing activity (ZPA) in limb development.

Oxysterols

Oxidized cholesterol derivatives that can result from enzymatic synthesis or chemical oxidation.

Protein self-splicing

In a class of autoprocessing proteins, removal of a middle segment, encoded by a mobile element, followed by ligation of the amino and carboxy termini through formation of a new peptide bond. The protein self-splicing reaction shares its initiating mechanism and a thioester intermediate with Hedgehog autoprocessing.

Resistance–nodulation–division (RND) transporters

A diverse family of transporters of substrates across cell membranes using chemiosmotic force, usually a proton gradient in prokaryotes and a Na+ gradient in eukaryotes. The family includes Patched and Dispatched of Hedgehog signalling.

SHH-N

The native N-terminal signalling domain of the Sonic hedgehog protein, modified by palmitoyl and cholesteryl lipid adducts at its N and C termini when produced in vivo by auto-processing (cholesteryl adduct) and enzymatic acylation (palmitoyl adduct).

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Zhang, Y., Beachy, P.A. Cellular and molecular mechanisms of Hedgehog signalling. Nat Rev Mol Cell Biol 24, 668–687 (2023). https://doi.org/10.1038/s41580-023-00591-1

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