Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Center for In Vivo Imaging and Therapeutics, Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun. 2020 Feb 14;11(1):912. doi: 10.1038/s41467-020-14628-y.
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.
脑室进行性扩大是几种神经和精神疾病的一个关键特征，其具体机制尚不清楚。在这里，我们使用与人类精神分裂症相关的 22q11 缺失综合征（22q11DS）的小鼠模型，发现侧脑室和第三脑室进行性扩大，室壁上的室管膜细胞纤毛的摆动速度减慢。在脑切片和体内观察到的纤毛摆动缺陷是由多巴胺受体（Drd1）水平升高引起的，而 Drd1 在运动纤毛中表达。微 RNA 加工基因 Dgcr8 的单倍不足导致 Drd1 升高，这是由于 Drd1 靶向微 RNA miR-382-3p 和 miR-674-3p 的减少所致。在 22q11DS 小鼠中补充任一种微 RNA 均可使纤毛摆动正常化，并使脑室大小正常化。敲低微 RNA 或在 Drd1 上缺失其种子序列可模拟纤毛摆动和脑室缺陷。这些结果表明，Dgcr8-miR-382-3p/miR-674-3p-Drd1 机制导致 22q11DS 中纤毛运动的减速和年龄依赖性脑室扩大。
