Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1242/dmm.050323

Type

Journal article

Journal

Dis Model Mech

Publication Date

01/02/2024

Volume

17

Keywords

CRISPR, Cerebellum, Development, Medulloblastoma, Patched 1, Sonic hedgehog, iPSCs, Humans, Mice, Animals, Medulloblastoma, Cerebellar Neoplasms, Patched-1 Receptor, Hedgehog Proteins, Induced Pluripotent Stem Cells, Cell Transformation, Neoplastic, Carcinogenesis, Organoids, Patched Receptors