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

Year: 2016
Type: preprint
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 n europsychiatric r isk g enes (NRGs) in a rapid and cost-effective manner 1 − 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 screening 10 . 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.
DOI: 10.1101/053900
Authors: Cristina Aguirre-Chen, Nuri Kim, Olivia Mendivil Ramos, Melissa Kramer, W. Richard McCombie, Christopher M. Hammell
Language: English
Subfield: Genetics
Open Access status: green
OpenAlex ID: W2403833259
Cites: 65
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Related to: 10