Human neuron subtype programming via single-cell transcriptome-coupled patterning screens by Hsiu-Chuan Lin, Jasper Janssens, Benedikt Eisinger, Philipp Hornauer, Ann-Sophie Kroell ISBN 10.1126/SCIENCE.ADN612 instant download

Human neuron subtype programming via single-cell transcriptome-coupled patterning screens by Hsiu-Chuan Lin, Jasper Janssens, Benedikt Eisinger, Philipp Hornauer, Ann-Sophie Kroell ISBN 10.1126/SCIENCE.ADN612 instant download

Human excitatory and inhibitory neurons can be To understand how morphogens influence the formation of induced from pluripotent stem cells (PSCs) in vitro through forced specific iN subtypes, we use scRNA-seq data to infer gene regulatory expression of pioneer transcription factors. These induced neurons networks. We identified key TFs and their downstream target genes, (iNs) are widely used for studying neural development, collectively called regulons, that are activated by combinations of differentiation, and neurological diseases such as Alzheimer’s morphogens to guide neurons into specific subtypes. To verify our disease, Parkinson’s disease, and amyotrophic lateral sclerosis. findings, we used genetic methods such as overexpression and In addition, programmed neurons show promise for cell replaceCRISPR-Cas9 knockouts to perturb key TFs. When key TFs are ment therapies to restore function after neurological damage. absent, morphogens can no longer direct iNs into specific subtypes. Systematic strategies to expand the diversity of neuron types is Conversely, overexpressing key TFs is sufficient to drive the essential for driving future breakthroughs.formation of specific iN subtypes without morphogens. We also found that exposing PSCs to morphogens before inducing RATIONALE: To create diverse neuron types in vitro, we propose that pro-neural TFs can activate regulons found in human neurons, broadly expressed pro-neural transcription factors (TFs), such as generating iN subtypes that are more uniform and more closely NGN2 and ASCL1 combined with morphogens, can guide regional resemble primary human neurons.