Hedgehog signalling: emerging evidence for non-canonical pathways

Area of Science:

• Developmental Biology
• Molecular Signaling
• Genetics

Background:

• The Hedgehog (HH) signaling pathway is fundamental for embryonic development in various species.
• Germline mutations in HH pathway components lead to congenital malformations in humans, while somatic mutations are linked to cancers.
• The canonical HH pathway involves GLI-mediated transcriptional regulation, but evidence for non-canonical signaling is emerging.

Purpose of the Study:

• To review and consolidate evidence supporting the existence of non-canonical Hedgehog signaling pathways.
• To highlight the complexity of HH signaling beyond the established canonical model.
• To encourage further research into non-canonical HH signaling mechanisms.

Main Methods:

• Review of existing literature on Hedgehog signaling.
• Analysis of genetic and biochemical studies in model organisms (Drosophila, C. elegans, mice).
• Examination of studies investigating HH pathway component interactions and functions independent of canonical pathways.

Main Results:

• Three scenarios for non-canonical HH signaling are proposed: GLI-independent signaling, cross-talk with other pathways, and atypical interactions among core HH components.
• Sonic hedgehog (SHH) has demonstrated roles in cell migration and axon guidance independent of canonical downstream effects.
• The HH receptor PTCH1 interacts with Cyclin B1 and caspases, influencing cell proliferation and apoptosis outside the canonical transcriptional response.

Conclusions:

• Collectively, the evidence suggests that non-canonical HH pathways exist and add complexity to HH signaling.
• Non-canonical pathways may function in parallel with canonical pathways, necessitating specific analytical approaches.
• Further investigation is crucial to fully elucidate the roles and mechanisms of non-canonical HH signaling.