Journal article
PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 6.9MB, Terms of use)
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- Publisher copy:
- 10.1242/dmm.050323
Authors
+ Brain Tumour Charity
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- Funder identifier:
- https://ror.org/01k33dw46
- Grant:
- P01 CA096832
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V037730/1
- Publisher:
- Company of Biologists
- Journal:
- Disease Models & Mechanisms More from this journal
- Volume:
- 17
- Issue:
- 2
- Article number:
- dmm050323
- Place of publication:
- England
- Publication date:
- 2024-02-27
- Acceptance date:
- 2024-02-06
- DOI:
- EISSN:
-
1754-8411
- ISSN:
-
1754-8403
- Pmid:
-
38411252
- Language:
-
English
- Keywords:
- Pubs id:
-
1663185
- Local pid:
-
pubs:1663185
- Deposit date:
-
2025-01-07
- ARK identifier:
Terms of use
- Copyright date:
- 2024
- Rights statement:
- © 2024. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
- Notes:
- This is a preprint of PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis.
- Licence:
- CC Attribution (CC BY)
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