Hedgehog Signaling in Development and Oncology

The Hedgehog (Hh) signalling pathway is a highly conserved mechanism that directs cell fate, patterning and tissue homeostasis throughout embryogenesis and adult life. Signalling is initiated when a secreted Hh ligand binds the Patched receptor (PTCH1), relieving suppression of the G-protein-coupled receptor Smoothened (SMO). Activated SMO triggers intracellular events that culminate in modulation of GLI transcription factors, which enter the nucleus to regulate genes controlling proliferation, differentiation and survival. In vertebrates, primary cilia provide a specialised compartment for Hh signal transduction, coordinating receptor trafficking and endocytic events. During development, Hh gradients act as morphogens to pattern the neural tube, limbs and craniofacial structures. In adults, low-level Hh activity maintains stem cell niches and tissue repair mechanisms. Aberrant Hh activation—through ligand overexpression, receptor mutations or non-canonical routes—drives oncogenesis in basal cell carcinoma, medulloblastoma and a range of solid tumours. Therapeutic efforts have focused on SMO antagonists, yet resistance mechanisms and pathway re-activation call for inhibitors targeting downstream effectors or intersecting pathways. The global impact of Hh-directed therapies spans inherited syndromes, radio-resistant brain tumours and metastatic disease, underscoring the pathway’s significance as both a developmental regulator and a cancer driver.

Research from Nature Portfolio

Recent studies have identified the endocytic adaptor Numb as a crucial regulator of Hh signalling at the ciliary pocket. Quantitative proteomics revealed Numb’s localisation at the base of the primary cilium, where it mediates clathrin-dependent removal of PTCH1 following ligand binding. Loss of Numb compromises PTCH1 exit from the cilium, dampening SMO activation and reducing transcriptional output. In vivo, ablation of Numb in neural progenitors impairs Sonic Hedgehog-driven cell fate decisions and diminishes proliferation of cerebellar granule cell precursors, leading to smaller cerebellar size. These findings highlight endocytic control at the ciliary pocket as a key switch in Hh signal activation and point to novel nodes for therapeutic intervention in Hh-dependent pathologies.

Hedgehog Signaling in Development and Oncology publication trend

The graph below shows the total number of articles in hedgehog signaling in development and oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Hedgehog signalling pathway: A cell-cell communication cascade in which Hedgehog ligands modulate receptor activity to control gene expression via GLI transcription factors.

Primary cilium: A microtubule-based organelle on the cell surface that organises components of the Hedgehog signalling cascade.

Patched (PTCH1): Twelve-pass transmembrane receptor that inhibits Smoothened in the absence of Hedgehog ligand.

Smoothened (SMO): Seven-pass transmembrane protein activated upon release from PTCH1 repression, transmitting signals to intracellular effectors.

GLI transcription factors: Zinc-finger proteins that regulate target gene transcription in response to Hedgehog pathway activity.

Non-canonical signalling: Activation of downstream effectors such as GLI independently of Smoothened, often mediated by alternative oncogenic pathways.

References

1. Hedgehog signaling in tissue homeostasis, cancers and targeted therapies. Signal Transduction and Targeted Therapy (2023).
2. The Inseparable Relationship Between Cholesterol and Hedgehog Signaling. Annual Review of Biochemistry (2023).
3. Numb positively regulates Hedgehog signaling at the ciliary pocket. Nature Communications (2024).
4. Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. Frontiers in Genetics (2019).