PTCH1mutant human cerebellar organoids are associated with altered neural development and early pathways of medulloblastoma oncogenesis

Abstract

SummaryPatched 1 (PTCH1) is the primary receptor for Sonic Hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations inPTCH1are associated with altered neuronal development and the malignant brain tumour medulloblastoma (MB). As a result of differences between murine and human development, molecular and cellular perturbations that arise from humanPTCH1mutations remain poorly understood. Here, we employ cerebellar organoids differentiated from human induced pluripotent stem cells (iPSC) combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences ofPTCH1mutations on human cerebellar development. Our findings support the occurrence of developmental mechanisms in cerebellar organoids that mirrorin vivoprocesses of regionalisation and SHH signalling, and offer new insight into early pathophysiological events of MB tumorigenesis.HiglightsDifferentiation of human iPSC into cerebellar organoidsHomozygous LOF ofPTCH1prevents cerebellar organoid differentiationPTCH1+/-cerebellar organoids display tissue-specific effects of SHH signallingEarly altered gene expression relevant for MB inPTCH1+/-cerebellar organoids