Schizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice

Tae-Yeon Eom,Linda Horner,Shondra M Pruett-Miller,Ben Wagner,Jieun Kim,Derek C Rose,Kara Anderson,Jing Yu,Yong-Dong Wang,Seung Baek Han,Stanislav S Zakharenko,Camenzind G Robinson,Jay A Blundon,Sadie Miki Sakurada,Damian B Kaminski,Matthew Eicholtz

doi:10.1038/s41467-020-14628-y

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.

Highlights

Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms
We observed a significant enlargement of the lateral ventricles (LVs) and third ventricle (TV) but no difference in the size of the fourth ventricle or the aqueduct in 8-month-old Df(16)1/+ mice compared to age-matched controls (Supplementary Table 1)
Similar results were achieved by measuring ventricle-to-brain ratios (VBRs), where ventricular volumes were normalized to the total brain volume (Supplementary Table 1ʹ)

Summary

Introduction

Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Knocking down the microRNAs or deleting their seed sites on Drd[1] mimicked the cilia-beating and ventricular deficits These results suggest that the Dgcr8–miR-382-3p/miR-674-3p–Drd[1] mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS. The progressive increase in the total or regional ventricular volumes usually becomes evident at the first episode of disease[17,18] Despite this strong linkage, the mechanisms of ventricular enlargement in psychiatric disorders are mostly unknown. We describe a novel pathogenic mechanism involving Dgcr8-dependent miRNA depletion in ependymal cells that leads to progressive decelerated motile ciliary beating and age-dependent ventricular enlargement in 22q11DS mouse models

Methods

Results

Conclusion