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PTCH1 -mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis
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PTCH1 -mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis
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Journal Article
PTCH1 -mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis
2024
Overview
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.
Publisher
The Company of Biologists
Subject
/ Cell Transformation, Neoplastic
/ Cerebellar Neoplasms - genetics
/ Cerebellar Neoplasms - metabolism
/ Cerebellar Neoplasms - pathology
/ crispr
/ Hedgehog Proteins - metabolism
/ Humans
/ Induced Pluripotent Stem Cells - metabolism
/ ipscs
/ Medulloblastoma - metabolism
/ Mice
/ Patched-1 Receptor - genetics
