ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

Abstract

There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using induced pluripotent stem cell (iPSC)-derived brain organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with ASD and their unaffected fathers in ten families. Relative to fathers, probands with macrocephaly presented an increase in dorsal cortical plate excitatory neurons (EN-DCP) to the detriment of preplate lineages, whereas normocephalic ASD probands presented an opposite decrease in EN-DCP-related gene expression. Both cohorts converged in a dysregulation of outer radial glia genes related to translation. In macrocephalic probands, an increase in progenitor self-renewal genes ID1/ID3 was coupled to a larger pool of cortical progenitors. Furthermore, changes in ID1/ID3 expression were best predictors of ASD clinical severity. We suggest that head circumference reveals a fundamental difference in etiological mechanisms of ASD rooted in alterations in progenitor fate and unbalanced excitatory cortical neuron diversity.

Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

“…However, we also extend our knowledge of cell types primarily affected by MIA, by showing that radial glia cells are specifically vulnerable to IL-6 signaling, shifting them towards a younger pseudoage along the neural differentiation trajectory. Finally, the brain organoid model of MIA may serve as a platform for investigating the effects of the interaction of genetic and environmental mediators of complex neurodevelopmental diseases such as ASD (59, 95, 96).…”

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

“…showing KRAB-ZNF gene enrichment and H3K9me3-mediated regulation in cell line-specific signatures suggest possible mechanisms controlling these stable expression phenotypes. Also regulated by H3K9me3 mechanisms, evolutionarily recent transposable elements and their corresponding KRAB-ZNF repressor genes have been directly implicated in human zygotic genome activation and preimplantation states specifying gene expression at later stages of development (65,(80)(81)(82)(83) The genetics of neurodevelopmental disorders (20,21,(84)(85)(86) and human brain evolution (18,(87)(88)(89) are being integrated into cerebral organoid models that parallel in utero and early postnatal brain development (90,91). As PSC-derived models of early human and mouse development become increasingly sophisticated (92)(93)(94)(95), approaches to exploring inherent variation across synthetic embryos from diverse PSC lines will become critical.…”

“…The urgency to address this need is illustrated by recent work reporting developmental differences between hPSC lines in generating regionally specified neural precursors and their possible implications in the etiology of neurodevelopmental disorders (14)(15)(16)(17)(18)(19)(20)(21). Here we employ cellular and genomic approaches to define functionally relevant variation in hPSC lines during in vitro morphogenesis as they traverse the earliest events in forebrain and hindbrain development.…”

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

“…These findings appear to be consistent with the recent study in organoids with SUV420H1, ARID1B, and CHD8 mutations [ 202 ]. Follow-up studies are beginning to further investigate this question using iPS lines derived from idiopathic ASD individuals who were either normocephalic or macrocephalic [ 207 ]. Phenotypic differences in progenitor cell development, neurogenesis, and neuronal differentiation between donors stratified according to macrocephaly status may provide important insights into neurodevelopmental phenotypes underlying patient phenotypes.…”