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Updated: Jul 2, 2025
Intracranial Orthotopic Allografting of Medulloblastoma Cells in Immunocompromised Mice
Published on: October 3, 2010
PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma
Max J van Essen1,2, Elizabeth J Apsley1,2, Joey Riepsaame3
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
Abstract:
Patched 1 (PTCH1) is the primary receptor for the sonic hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations in PTCH1 are associated with altered neuronal development and the malignant brain tumour medulloblastoma. As a result of differences between murine and human development, molecular and cellular perturbations that arise from human PTCH1 mutations remain poorly understood. Here, we used cerebellar organoids differentiated from human induced pluripotent stem cells combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences of PTCH1 mutations on human cerebellar development. Our findings demonstrate that developmental mechanisms in cerebellar organoids reflect in vivo processes of regionalisation and SHH signalling, and offer new insights into early pathophysiological events of medulloblastoma tumorigenesis without the use of animal models.
Insights
Patched 1 (PTCH1) mutations disrupt human cerebellar development by altering sonic hedgehog (SHH) signaling. This study uses human organoids to reveal early medulloblastoma development insights without animal models.
Area of Science:
- Developmental Biology
- Neuroscience
- Cancer Research
Background:
- Patched 1 (PTCH1) is the sonic hedgehog (SHH) receptor, crucial for human embryogenesis.
- PTCH1 loss-of-function mutations link to neuronal development issues and medulloblastoma.
- Human PTCH1 mutation effects are poorly understood due to developmental differences from mice.
Purpose of the Study:
- Investigate early molecular and cellular impacts of PTCH1 mutations in human cerebellar development.
- Utilize human induced pluripotent stem cells and CRISPR/Cas9 gene editing.
- Model early medulloblastoma pathogenesis without animal models.
Main Methods:
- Differentiated human induced pluripotent stem cells into cerebellar organoids.
- Employed CRISPR/Cas9 gene editing to introduce PTCH1 mutations.
- Analyzed developmental mechanisms and SHH signaling pathways.
Main Results:
- Cerebellar organoids recapitulate in vivo human cerebellar regionalization.
- Observed alterations in SHH signaling due to PTCH1 mutations.
- Identified early cellular events relevant to medulloblastoma.
Conclusions:
- Human cerebellar organoids are a viable model for studying developmental disorders.
- PTCH1 mutations initiate early pathological events in medulloblastoma.
- This model provides insights into human-specific developmental consequences of PTCH1 mutations.
