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

Tae-Yeon Eom, Seung Baek Han, Jieun Kim, Jay A. Blundon, Yong-Dong Wang, Jing Yu, Kara Anderson, Bogumił Kamiński, Sadie Miki Sakurada, Shondra M. Pruett-Miller, Linda Horner, Ben Wagner, Camenzind G. Robinson, Matthew Eicholtz, Derek C. Rose and Stanislav S. Zakharenko ()
Additional contact information
Tae-Yeon Eom: St. Jude Children’s Research Hospital
Seung Baek Han: St. Jude Children’s Research Hospital
Jieun Kim: Center for In Vivo Imaging and Therapeutics, Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital
Jay A. Blundon: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Jing Yu: St. Jude Children’s Research Hospital
Kara Anderson: St. Jude Children’s Research Hospital
Sadie Miki Sakurada: Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital
Linda Horner: Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital
Ben Wagner: Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital
Camenzind G. Robinson: Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital
Matthew Eicholtz: Electrical and Electronics Systems Research Division, Oak Ridge National Laboratory
Derek C. Rose: Electrical and Electronics Systems Research Division, Oak Ridge National Laboratory
Stanislav S. Zakharenko: St. Jude Children’s Research Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14628-y

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