Work

Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids

Year: 2023

Type: article

Abstract: PTENgermline mutations account for ~ 1% of all autism spectrum disorder (ASD) cases, as well as ~ 17% of ASD patients with macrocephaly, making it one of the top ASD associated risk genes. Individuals with germlinePTENmutations receive the molecular diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), an inherited cancer predisposition syndrome, about 20–23% of whom are diagnosed with ASD. We generated forebrain organoid cultures from gene-edited isogenic human induced pluripotent stem cells (hiPSCs) harboring aPTENG132D(ASD) orPTENM134R(cancer) mutant allele to model how these mutants interrupt neurodevelopmental processrf. Here, we show that thePTENG132Dallele disrupts early neuroectoderm formation during the first several days of organoid generation. While organoids generated fromPTENM134RhiPSCs remained morphologically similar to wild-type organoids during this early stage in development, we observed disrupted neuronal differentiation, radial glia positioning, and cortical layering in bothPTENmutant organoids at the later stage of 72 + days of development. Perifosine, an AKT inhibitor, reduced over activated AKT and partially corrected the abnormalities in cellular organization observed inPTENG132Dorganoids. Single cell RNAseq analyses on early-stage organoids revealed that genes related to neural cell fate was least enriched inPTENG132Dmutant organoids, and AKT inhibition was capable of upregulating gene signatures related to neuronal cell fate and CNS maturation pathways. These findings demonstrate that differentPTENmissense mutations can have profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on the way to mitigate pathological impact ofPTENmutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components.

Source: Molecular Psychiatry

DOI: 10.1038/s41380-023-02325-3

Authors: Shin Chung Kang, Nicholas B. Sarn, Juan Venegas, Zhibing Tan, Masahiro Hitomi, Charis Eng