16p11.2 deletion accelerates subpallial maturation and increases variability in human iPSC-derived ventral telencephalic organoids

Abstract

Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence marker expression at early developmental timepoints, and expression of the neuronal marker NEUN at later stages. At early stages, deletion organoids exhibited greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker COUPTFII, with increased variability in these properties. Cell cycle analysis revealed an increase in total cell cycle length caused primarily by an elongated G1 phase, the duration of which also varied more than normal. At later stages, deletion organoids increased their NEUN expression. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.

Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

“…To date, two studies employed cerebral organoids to investigate the effects of the 16p11.2 deletion on brain development ( Urresti et al, 2021 ; Fetit et al, 2023 ). Importantly, DEL and DUP cortical organoids could recapitulate the brain size phenotypes.…”

“…The effects of 16p11.2 CNVs on interneurons development was recently investigated by Fetit et al Ventral organoids harbouring the 16p11.2 deletion were more variable in size compared with the isogenic controls ( Fetit et al, 2023 ). This variability could be relevant when considering the clinical heterogenicity of DEL human carriers ( Fetit et al, 2020 ).…”

“…This variability could be relevant when considering the clinical heterogenicity of DEL human carriers ( Fetit et al, 2020 ). In addition, the authors found a substantial acceleration of subpallial development in DEL organoids, potentially leading to premature differentiation ( Fetit et al, 2023 ).…”