Abstract
Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8–miR-382-3p/miR-674-3p–Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.
Original language | English |
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Article number | 912 |
Journal | Nature Communications |
Volume | 11 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2020 |
Funding
We thank the members of the Zakharenko lab for providing comments, Angela McArthur for editing the manuscript, Chris Fiveash for assisting with the artwork, Scott Olsen and Geoff Neale for assisting with the miRNA microarray experiments, Dennis Jay and the St. Jude Pathology Laboratory for measuring CSF osmolarity, Abbas Shirinifard Pilehroud for assistance with the statistical analysis of planar polarity and editing of movies, Valerie Stewart and Kristen Correia for generating mutant mice, Kristen Phend and Richard Weinberg (University of North Carolina–Chapel Hill) for developing the embedding method. Michael Holtzman (Washington University) and David Clapham (Harvard University) for the gift of Foxj1Cre mice and Arl13bGFP mice, respectively. This work was supported by the National Institutes of Health grant R01 MH097742 and ALSAC (S.S.Z.) and a Garwood postdoctoral fellowship and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (T.-Y.E.). St. Jude Shared Resources are supported by St. Jude and NCI P30 CA021765. The funding sources had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript.