Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF

IF 11.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nanxi Zheng, Shilin Luo, Xin Zhang, Ling Hu, Muzhi Huang, Mingyu Li, Colin McCaig, Yu-Qiang Ding, Bing Lang
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引用次数: 0

Abstract

Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms. We performed a battery of behavioral tests with haploinsufficiency () and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by mice. mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression. Our data suggest that Ift172 drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders.
鞘内转运蛋白 172 的单倍体缺陷通过 BDNF 导致小鼠出现类似自闭症的行为表型
原发性纤毛是生长在大多数哺乳动物细胞上的毛发状单细胞器,在胚胎形态和器官形成过程中发挥着重要作用。纤毛缺陷通常会导致一系列遗传性疾病,这些疾病被称为纤毛疾病,具有多方面的表现。纤毛内运输(IFT)是一种沿纤毛的双向蛋白质运输,能积极促进初级纤毛的形成和吸收。IFT172 是 IFT-B 复合物中最大的成分,它在巴尔德-比德尔综合征(BBS)中的作用已得到重视,但其机制尚不清楚。我们用单倍体缺陷()和 WT 胎鼠进行了一系列行为测试。我们利用 RNA 测序来确定小鼠海马中差异表达和富集的基因和信号通路。利用 AAV 介导的稀疏标记、电子显微镜检查、膜片钳和局部场电位记录、Western 印迹、荧光素酶报告分析、染色质免疫沉淀和神经药理学方法,我们研究了小鼠异常表型的潜在机制。RNA 测序显示,轴突生成和突触可塑性相关通路中的差异表达基因富集,脊柱密度和突触数量的减少进一步证实了这一点。小鼠表现出较少的parvalbumin表达神经元、抑制性突触传递减少、θ振荡增强以及CA1区域的尖波涟漪。此外,单倍体缺陷导致 BDNF 生成减少,通过转录因子 Gli3 激活的 BDNF-TrkB 信号通路减少。应用7,8-二羟基黄酮(一种强效的小分子TrkB激动剂)可完全恢复小鼠的BDNF-TrkB信号活性和异常行为表型。通过荧光素酶和芯片检测,我们进一步证明了 Gli3 可能与 BDNF 启动子 I 发生物理作用并调控 BDNF 的表达。我们的数据表明,Ift172 可驱动神经营养效应,如果存在缺陷,则可能导致类似自闭症的神经发育障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Advanced Research
Journal of Advanced Research Multidisciplinary-Multidisciplinary
CiteScore
21.60
自引率
0.90%
发文量
280
审稿时长
12 weeks
期刊介绍: Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.
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