Hedgehog signaling: mechanisms and evolution

Abstract

The Hedgehog (Hh) family of secreted proteins plays essential roles in the development of a wide variety of animal species and underlies multiple human birth defects and cancers. To ensure the proper range of signaling, the Hh proteins are modified with lipids, assembled into water-soluble multimers, and interact with multiple cell surface proteins. In the target cells, a largely conserved intracellular signal transduction pathway, from the cell surface receptor Patched to the Glioma-associated oncogene homolog (Gli) family of transcription factors, mediates the transcriptional responses from fruit flies to mammals. A significant divergence between vertebrates and insects is the vertebrate-specific requirement of cilia for Hh signal transduction and Gli protein activation. Finally, transcription-independent cellular responses to Hh have been described in certain developmental processes. With clinical trial underway to treat Hh-related diseases, more work is urgently needed to reach a more comprehensive understanding of the molecular mechanisms underlying the regulation of Hh signaling in development and diseases.

Keywords

Hedgehog / Shh / Ihh / Dhh / Cubitus interruptus (Ci) / Gli1 / Gli2 / Gli3 / Patched / Smoothened / Cilia / Drosophila / mouse / signaling / development / evolution

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Acknowledgment

We thank Westley Heydeck, Huiqing Zeng and Jinling Liu for critically reading the manuscript. We apologize to colleagues whose work we failed to include in this short review because of the huge amount of information published in this field. Research activities in our laboratory are supported by grants from NSF, American Heart Association, PKD foundation and a new laboratory start-up fund from the Pennsylvania State University.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg