Jubierre, L. | bioRxiv Science

bioRxiv2024

Cortical assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects

Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during brain development remains poorly understood. The protracted maturation of these cells during postnatal life has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding hPSC-based disease modeling of their role in neuropsychiatric disease. Here we present a cortical assembloid system that supports the development of PVALB+ cortical interneurons which match the molecular profiles of primary PVALB+ interneurons and display their distinctive electrophysiological features. Further, we characterized cortical interneuron development in a series of CRISPR-generated isogenic structural variants associated with schizophrenia and identified variant-specific phenotypes affecting cortical interneuron migration and the molecular profile of PVALB+ cortical interneurons. These findings offer plausible mechanisms on how the disruption of cortical interneuron development may impact schizophrenia risk and provide the first human experimental platform to study of PVALB+ cortical interneurons.

neuroscience↗

bioRxiv2022

Childhood cancer mutagenesis caused by a domesticated DNA transposase

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer. One-Sentence SummaryInduction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.

cancer biology↗