Developmental and cell type-specific origin of autism pathology at single-cell resolution
- Awarded: 2020
- Award Type: Pilot
- Award #: 724430
Autism spectrum disorders (ASDs) represent a heterogeneous group of neurodevelopmental conditions with a strong genetic basis. Despite their considerable genetic heterogeneity, they are often characterized by convergent neuropathological features, including abnormal cortical development or disrupted synaptic homeostasis. Most of these features have been identified in animal models or in postmortem studies, raising the question of how ASD-relevant mutations give rise to those neuropathological changes in a human context. Analyzing when, how, and in which cell types ASD pathology arises within the human brain will require a genetically tractable model system that can mimic human embryonic and fetal brain development.
Organoid models have been used to recapitulate disease-relevant defects in cell fate specification, proliferation, cell migration and overall tissue morphology (e.g., 1). For the brain in particular, the enormous improvement of single-cell transcriptomics has facilitated rapid, detailed and reproducible phenotypic analysis in cerebral organoids. The goal of this project is to annotate high-risk ASD-relevant genes by analyzing their loss-of-function phenotypes in cerebral organoids at the single-cell level.
Building on the recently established inducible CRISPR/Cas9 brain organoid screening platform2, Jürgen Knoblich and his colleagues will combine pooled genetic perturbations with single-cell RNA transcriptomics in order to investigate the developmental and cell type-specific origin of ASD pathology. By correlating single-cell genotypes and phenotypes, they aim to generate a comprehensive snapshot of transcriptomic changes that occur as a result of loss-of-function mutations in high-risk ASD genes. They plan to analyze cellular phenotypes across different developmental stages, cell types and brain regions to uncover novel cell-type specific or convergent pathophysiological mechanisms and ultimately shed light on the developmental origin of ASD.
The ultimate goal of the project is to create a unique and comprehensive resource for the ASD research community to facilitate the discovery of cell type-specific mechanisms and identify novel convergent molecular pathways.