Cerebral organoids containing an AUTS2 missense variant model microcephaly

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Variants in the AUTS2 gene are linked to neurological conditions including intellectual disability, microcephaly, and brain malformations.
• AUTS2 syndrome encompasses a range of neurodevelopmental impairments.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms of a de novo heterozygous missense AUTS2 variant using human cerebral organoids.
• To understand the role of AUTS2 in human cortical development and neural progenitor cell function.

Main Methods:

• Utilized human cerebral organoids derived from a patient with a de novo AUTS2 variant.
• Employed CRISPR-Cas9 gene editing to correct the identified AUTS2 variant.
• Performed single-cell RNA sequencing (scRNA-seq) on patient-derived and control organoids.

Main Results:

• Proband cerebral organoids showed reduced growth, impaired neural progenitor cell (NPC) proliferation, and disrupted NPC polarity.
• CRISPR-Cas9 correction of the AUTS2 variant rescued organoid growth and NPC proliferation deficits.
• scRNA-seq identified reduced G1/S transition gene expression and altered WNT-β-catenin signaling in patient-derived NPCs.

Conclusions:

• AUTS2 plays a critical role in regulating NPC proliferation and polarity during human cortical development.
• Human cerebral organoids serve as a valuable model for studying the molecular basis of AUTS2 syndrome.
• The findings elucidate novel mechanisms by which AUTS2 variants lead to neurodevelopmental deficits.