Regulation of Hedgehog Signalling Inside and Outside the Cell.

Simon Ramsbottom,Mary Pownall

doi:10.3390/jdb4030023

Simon Ramsbottom, Mary Pownall

Open Access

https://doi.org/10.3390/jdb4030023

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Abstract

The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction.

Highlights

Hedgehog was originally identified as a segment polarity gene in Drosophila [1]
While this finding was made in mice, the complex machinery of kinases and microtubule-associated proteins involved in the intracellular relay of the hedgehog signal were largely dissected genetically in Drosophila; again, an unbiased genetic approach was essential for the discovery of many components of the Hh signal transduction pathway
Disp-dependent fashion and be internalised by endosomal sorting sheddases, which remove cholesterol and palmitate. These complexes are more soluble than the complexes required for transport (ESCRT) proteins, which sort Hh proteins into intra-luminal monomeric form and so are able to diffuse away from the cell; (2) Unprocessed Hh may re-enter the cell in a Disp-dependent fashion (2a) and be internalised by endosomal sorting complexes required for transport (ESCRT) proteins, which sort Hh proteins into intra-luminal vesicles (2b); These vesicles subsequently fuse with the plasma membrane and are released from the cell (2c); (3) Association of Hh with Heparan sulfate proteoglycans (HSPGs) results in loading of Hh into lipoprotein particles

Summary

Introduction

Hedgehog (hh) was originally identified as a segment polarity gene in Drosophila [1]. The recognition that primary cilia serve as a signalling hub was an unexpected finding from a forward genetic screen for embryonic patterning defects similar to the Shh mutant phenotype [6]. While this finding was made in mice, the complex machinery of kinases and microtubule-associated proteins involved in the intracellular relay of the hedgehog signal were largely dissected genetically in Drosophila; again, an unbiased genetic approach was essential for the discovery of many components of the Hh signal transduction pathway. This review will focus on the regulation of canonical hedgehog signalling, from expression of the ligand through to the activation of target genes

Hedgehog Expression

Ligand Synthesis

Ligand Release and Dispersal

Heparan Sulfate Proteoglycans

Regulation by SULF1

Regulation at the Membrane

Downstream of Smo

The Primary Cilium

10. Perspectives