한빛사 논문
Tae-Yeon Eom1,8, Seung Baek Han1,8, Jieun Kim2, Jay A. Blundon1, Yong-Dong Wang3, Jing Yu1, Kara Anderson1, Damian B. Kaminski1, Sadie Miki Sakurada4, Shondra M. Pruett-Miller4, Linda Horner5, Ben Wagner5, Camenzind G. Robinson5, Matthew Eicholtz6,7, Derek C. Rose6 & Stanislav S. Zakharenko1
1Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 2Center for In Vivo Imaging and Therapeutics, Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 3Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 4Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 5Cellular Imaging Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 6Electrical and Electronics Systems Research Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. 7Present address: Department of Computer Science, Florida Southern College, Lakeland, FL 33801, USA. 8These authors contributed equally: Tae-Yeon Eom, Seung Baek Han.
*Correspondence to Stanislav S. Zakharenko
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.
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