A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes

Abstract

Highlights d hPSC-based multiplex platform for interrogation of autismassociated mutations d Prefrontal cortex paradigm in hPSCs identifies autism-related neurogenesis defects d Abnormal WNT/bcatenin responses in class of autism genes with neurogenesis defects d Endophenotypes in hPSCs correlate with clinical data in autism patients

SARS-CoV-2 infects human neural progenitor cells and brain organoids

“…During the submission process of this manuscript, the susceptibility of human brain organoid was similarly suggested by two independent studies. 10 , 11 However, the permissiveness of neuronal progenitor cells to SARS-CoV-2 was not evaluated in these studies. 10 , 11 We demonstrated here that SARS-CoV-2 could also target the neuronal progenitor cell populations.…”

“…10 , 11 However, the permissiveness of neuronal progenitor cells to SARS-CoV-2 was not evaluated in these studies. 10 , 11 We demonstrated here that SARS-CoV-2 could also target the neuronal progenitor cell populations. In this regard, the recovery of the olfactory function and other neurological manifestations might be incomplete and late as these neural progenitor cells could be infected by SARS-CoV-2.…”

The phenomenal epigenome in neurodevelopmental disorders

“…Previous integrated analysis of six exome studies uncovered a network of genes mutated in autism spectrum disorder (ASD) and ID highlighting proteins converging on β-catenin as a part of the WNT signaling pathway ( 41 ). In support of this, a recent study defined molecular and functional subclasses within a set of 30 autism-related genes (in fact better defined as NDD genes) based on the in vitro neurogenic potency of pluripotent stem cells carrying engineered mutations in these genes ( 42 ). This identified a class of eight genes with mutations associated with increased proliferation and inhibited neurogenesis (class 1 comprising chromatinopathy genes ASH1L , ASXL3 KDM5B and KMT2C ).…”

“…It should be noted, however, that the study of Cederquist et al . ( 42 ) also uncovered a smaller class of genes with the opposite neurogenic effects, which did not have an altered WNT response despite the fact that two chromatinopathy genes from this class, KMT2A and CHD8 , are also regulators of polycomb. Moreover, mutations in these genes have variable growth defects in patients.…”

Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets

“…Another interesting application of recent advances in pooled RNA-seq technology is represented by systematic sequencing of villages of neurons obtained from patientderived iPSCs [129,130]. For instance, Cederquist and colleagues, pooled in a single dish 30 isogenic iPSC lines harboring de novo ASD mutations to disentangle ASD genetic heterogeneity [131]. The same approach can be used to explore polygenic risk or to assess the impact of genetic background on ASD-relevant phenotypes and eQTLs (expression quantitative trait loci).…”