Trends in Cell Biology
Volume 12, Issue 12, 1 December 2002, Pages 562-569
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Review
Pathways and consequences: Hedgehog signaling in human disease

https://doi.org/10.1016/S0962-8924(02)02405-4Get rights and content

Abstract

Signaling pathways that play a fundamental role during development are turning out to underlie many disease states when misregulated. Here, we review some of the recent findings in the Hedgehog (Hh) pathway and the role it plays in different human diseases. We present a summary of the diseases that result from the inactivation or inappropriate activation of the Hh pathway. The human phenotypes generally fit the findings in model organisms and help to identify some potential targets for therapy.

Section snippets

The Hedgehog pathway: an overview

Several of the components of the Hh pathway were first identified in flies and later described in vertebrates (reviewed in 1., 2.). The interactions between these different components constitute, in part, a chain of consecutive repressive events that finally results in a modification of gene transcription (see Fig. 1). Hh, an extracellular ligand, is secreted by discrete subsets of cells in many organs and is processed in the expressing cell through an autocatalytic reaction that removes the

The role of Hh in animal development

Three homologs of Hh have been described in mammals: Sonic (Shh), Indian (Ihh) and Desert (Dhh) hedgehogs. Although most studies have been performed with Shh, all three might work similarly [12] – but in different contexts. Thus, it is likely that mutations in any of the components of the pathway will affect signaling from all three Hh proteins. Different roles have been described for Shh during development, acting as a morphogen, mitogen or differentiation factor. For example, there is a

The SHH gene in forebrain development and cancer

Patients carrying heterozygous mutations in SHH present holoprosencephaly (HPE) and Shh−/− mice display cyclopia (reviewed in 19., 20.). HPE affects the forebrain and face to various degrees, from the most extreme lethal alobar type to milder microforms that include small midline facial defects. Interestingly, a missense mutation in the SHH gene is associated with a variable phenotype within the same family, from alobar HPE to subtle defects including attention deficiencies [21]. This raises

Pathways and therapies

Looking at the human HH pathway from a different perspective, we can see whether mutations in the various elements of the pathway cause the same diseases (Table 1; Fig. 3). Clearly, alterations in different components of the HH pathway can lead to different phenotypes, although there is a good degree of consistency, implying the linearity of the pathway. For example, on the one hand, alterations in several loci have been associated with HPE in humans and at least five genes have been identified

Acknowledgements

We thank Barbara Stecca, Yorick Gitton, Jessica Treisman, Verónica Palma and Van Nguyen for comments on the review and discussion. Owing to space limitations, we could not reference the important work of many colleagues.

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