Amplification of human interneuron progenitors promotes brain tumors and neurological defects

Abstract

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.

Cellular stress in brain organoids is limited to a distinct and bioinformatically removable subpopulation

“…We reanalyzed recent, landmark single cell transcriptomics studies and performed new experiments (Bhaduri et al, 2020; Eichmüller et al, 2022; Kanton et al, 2019; Khan et al, 2020; Velasco et al, 2019) ( Fig 1A ) to answer 3 questions: What stress pathways are active in organoids? Does stress occur in all or only certain organoid protocols?…”

“…Besides a lack of cell type specification, incomplete maturation due to stress was previously suggested (Bhaduri et al, 2020). As a positive control for maturation, we took two media conditions that affected maturation (Eichmüller et al, 2022). We grew pairwise matched samples in two different media conditions, then analyzed together ( Fig 4G ).…”

“…We used the following public datasets for this study: dbGaP Study Accession: phs001836.v1.p1. (Polioudakis et al 2019; de la Torre-Ubieta et al 2018); ENA PRJEB33917 (Kanton et al 2019) ; GEO GSE132672 (Bhaduri et al 2020); EGA EGAD00001006332 (Eichmüller et al 2022); GEO GSE129519 (Velasco et al 2019).…”

“…The single-cell RNA-sequencing data have been uploaded to Gene Expression Omnibus (GEO) under reference number GSE1XXXXXXXXX (ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE1XXXXXXXXX). We used publicly available raw sequencing data from the following publications (Bhaduri et al, 2020; Eichmüller et al, 2022; Kanton et al, 2019; Polioudakis et al, 2019, 2019; Velasco et al, 2019) and obtained wild type patient data from the authors of, complying with ethical and data safety requirements (Khan et al, 2020; Samarasinghe et al, 2021). The Gruffi package will be available under github.com/jn-goe/gruffi.…”

Accounting for cis-regulatory constraint prioritizes genes likely to affect species-specific traits

“…Based on this, the change in EDNRB expression may have promoted human brain expansion by increasing the proliferation of the subpopulation of radial glia that express EDNRB . In addition, a recent study identified a population of caudal late interneuron progenitor (CLIP) cells marked by expression of EDNRB and PTGDS along with caudal ganglionic eminence markers (Eichmüller et al 2022). As both EDNRB and PTGDS have strongly human-biased ASE it would be interesting to investigate if this population of cells exists in chimpanzee brain organoids and if it may have expanded in humans.…”