Protocol for neurogenin-2-mediated induction of human stem cell-derived neural progenitor cells

Guss, Ellen J.; Sathe, Laila; Dai, Alexander; Derebenskiy, Tim; Vega, Ana Rodriguez; Eggan, Kevin; Wells, Michael F.

doi:10.1016/j.xpro.2024.102878

STAR Protocols

2024

DOI: 10.1016/j.xpro.2024.102878

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Protocol for neurogenin-2-mediated induction of human stem cell-derived neural progenitor cells

Ellen J. Guss,

Laila Sathe,

Alexander Dai

et al.

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2024

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Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Gordon,

Yoon,

Bicks

et al. 2024

Preprint

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Two decades of genetic studies in autism spectrum disorder (ASD) have identified over a hundred genes harboring rare risk mutations. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across ASD post-mortem brain tissue. To identify shared and distinct mutational mechanisms, we assembled the largest hiPS cell patient cohort to date, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected controls. We used these hiPS lines to generate human cortical organoids (hCO), profiling by RNAseq at four distinct timepoints up to 100 days of in vitro differentiation. Early timepoints harbored the largest mutation-specific changes, but different genetic forms converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed down-stream changes in gene expression. CRISPR-Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream molecular convergent effects. These data illustrate how genetic risk can propagate via transcriptional regulation to impact convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment.

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Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Gordon,

Yoon,

Bicks

et al. 2024

Preprint

View full text Add to dashboard Cite

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Dynamic convergence of autism disorder risk genes across neurodevelopment

Fernandez Garcia,

Retallick-Townsley,

Pruitt

et al. 2024

Preprint

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Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention.

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Protocol for neurogenin-2-mediated induction of human stem cell-derived neural progenitor cells

Cited by 2 publications

References 5 publications

Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Dynamic convergence of autism disorder risk genes across neurodevelopment

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