C. elegans PVD Neurons: A Platform for Functionally Validating and Characterizing Neuropsychiatric Risk Genes

Abstract

One of the primary challenges in the field of psychiatric genetics is the lack of an in vivo model system in which to functionally validate candidate neuropsychiatric risk genes (NRGs) in a rapid and cost-effective manner1-3. To overcome this obstacle, we performed a candidate-based RNAi screen in which C. elegans orthologs of human NRGs were assayed for dendritic arborization and cell specification defects using C. elegans PVD neurons. Of 66 NRGs, identified via exome sequencing of autism (ASD)4 or schizophrenia (SCZ)5-9 probands and whose mutations are de novo and predicted to result in a complete or partial loss of protein function, the C. elegans orthologs of 7 NRGs were found to be required for proper neuronal development and represent a variety of functional classes, including transcriptional regulators and chromatin remodelers, molecular chaperones, and cytoskeleton-related proteins. Notably, the positive hit rate, when selectively assaying C. elegans orthologs of ASD and SCZ NRGs, is enriched >14-fold as compared to unbiased RNAi screening10. Furthermore, we find that RNAi phenotypes associated with the depletion of NRG orthologs is recapitulated in genetic mutant animals, and, via genetic interaction studies, we show that the NRG ortholog of ANK2, unc-44, is required for SAX-7/MNR-1/DMA-1 signaling. Collectively, our studies demonstrate that C. elegans PVD neurons are a tractable model in which to discover and dissect the fundamental molecular mechanisms underlying neuropsychiatric disease pathogenesis.