Cerebral organoids containing an AUTS2 missense variant model microcephaly.
Summer R FairWesley SchwindDominic JulianAlecia BielGongbo GuoRyan RutherfordSwetha RamadesikanJesse WestfallKatherine E MillerMeisam Naeimi KararoudiScott E HickeyTheresa Mihalic MosherKim L McBrideReid NeinastJames FitchDean LeePeter WhiteRichard K WilsonTracy A BedrosianDaniel C KoboldtMark E HesterPublished in: Brain : a journal of neurology (2022)
Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband COs exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control COs. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-Catenin signaling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of COs to investigate molecular mechanisms underlying AUTS2 syndrome.
Keyphrases
- intellectual disability
- single cell
- autism spectrum disorder
- gene expression
- endothelial cells
- crispr cas
- cerebral ischemia
- induced pluripotent stem cells
- rna seq
- subarachnoid hemorrhage
- traumatic brain injury
- copy number
- heart failure
- resting state
- stem cells
- pluripotent stem cells
- genome editing
- dna methylation
- cell proliferation
- signaling pathway
- functional connectivity
- white matter
- early onset
- brain injury
- blood brain barrier
- single molecule