Published on December 19, 2018 | Updated on January 29, 2019

CORTEX conference by James Ellis

March 31st, 2017

iPS cell models of autism spectrum disorder and post-transcriptional gene regulation during human neurodevelopment

Induced pluripotent Stem Cells (iPSC) derived from subjects with neurodevelopmental disorders produce affected neurons to model disease and screen drugs in vitro. We use iPSC from subjects with Autism Spectrum Disorder (ASD), and CRISPR genome editing of the same genes, to evaluate neuronal phenotypes. We observe under-connectivity in neurons with mutations in PTCHD1-AS, thereby linking this long non-coding (lnc)RNA with neuronal function and ASD. In contrast, a sparse co-culture method developed to overcome inter-line heterogeneity reveals an ASD-associated over-connectivity phenotype in SHANK2 mutated neurons. We also use iPSC to investigate post-transcriptional regulation of disease-associated genes during human neurodevelopment. For example, RNA binding proteins and microRNAs target MECP2 transcripts to degrade them and regulate translation (Rodrigues et al, Cell Reports 2016). Ultimately, our ongoing studies of altered post-transcriptional regulation in Rett syndrome neurons may identify dysregulated proteins that provide novel insight into disease mechanisms and potential therapies.