PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis

Dis Model Mech. 2024 Feb 1;17(2):dmm050323. doi: 10.1242/dmm.050323. Epub 2024 Feb 27.


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.

Keywords: CRISPR; Cerebellum; Development; Medulloblastoma; Patched 1; Sonic hedgehog; iPSCs.

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Transformation, Neoplastic
  • Cerebellar Neoplasms* / genetics
  • Cerebellar Neoplasms* / metabolism
  • Cerebellar Neoplasms* / pathology
  • Hedgehog Proteins / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Medulloblastoma* / genetics
  • Medulloblastoma* / metabolism
  • Medulloblastoma* / pathology
  • Mice
  • Organoids / metabolism
  • Patched Receptors
  • Patched-1 Receptor / genetics
  • Patched-1 Receptor / metabolism


  • Patched-1 Receptor
  • Hedgehog Proteins
  • Patched Receptors