Neuronal primary cilia in dopamine receptor 1 signaling

 描述(申请人提供)：初级纤毛是典型的单生的、不活动的细胞附属物，几乎从所有哺乳动物细胞类型伸出。它们提供重要的感觉和信号功能，而初级纤毛的形成或功能缺陷会导致一类人类疾病，称为纤毛病。由于原发纤毛的普遍存在，纤毛疾病与广泛的临床特征有关，包括囊性肾疾病、视网膜变性、肥胖、骨骼缺陷、性腺功能减退、嗅觉障碍、行为障碍、社会缺陷和智能障碍。与纤毛疾病相关的一系列神经疾病表明，纤毛在大脑中发挥着重要作用。事实上，哺乳动物大脑中的大多数神经元都有一个初级纤毛，它富含特定的G蛋白偶联受体(GPCRs)，如多巴胺受体1(D1)。据认为，神经元纤毛感受神经调节剂，并提供专门的信号。然而，初级纤毛在神经元功能中的作用在很大程度上仍不清楚。我们发现，在人类纤毛病Bardet-Biedl综合征(BBS)的小鼠模型中，GPCRs进出神经元纤毛的运输是动态的，GPCR纤毛定位的调节被扰乱。例如，D1在BBS小鼠的纹状体和杏仁核神经元上显示纤毛异常堆积。有趣的是，这些小鼠表现出运动活动减少和成年后出现肥胖；这些表型与缺陷的D1信号一致。我们假设，GPCRs进出纤毛协调受体信号，纤毛定位的中断改变了GPCRs信号的调节。本研究的目的是确定D1纤毛的聚集和丢失对D1纤毛的表达、运输和信号传递的影响。这项工作的结果有望从根本上促进我们对纤毛在调控D1信号中的作用的理解。这些研究将提供对纤毛信号的关键见解，这是建立GPCR在整个大脑神经元纤毛定位的重要性所必需的。

 DESCRIPTION (provided by applicant): Primary cilia are typically solitary, immotile cellular appendages that project from nearly all mammalian cell types. They provide important sensory and signaling functions and defects in the formation or function of primary cilia leads to a class of human diseases called ciliopathies. Due to the ubiquity of primary cilia, ciliopathies are associated with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, skeletal defects, hypogonadism, anosmia, behavioral disturbances, social deficits and intellectual disability. The range of neurological disorders associated with ciliopathies indicates that cilia play important roles in the brain. In fact, most neurons throughot the mammalian brain possess a primary cilium that is enriched for specific G protein-coupled receptors (GPCRs), such as dopamine receptor 1 (D1). It is thought that neuronal cilia sense neuromodulators and provide specialized signaling. Yet, the roles of primary cilia in neuronal function remain largely unknown. We have discovered that trafficking of GPCRs to and from neuronal cilia is dynamic and regulation of GPCR ciliary localization is disrupted in mouse models of the human ciliopathy Bardet-Biedl syndrome (BBS). For example, D1 shows abnormal accumulation in cilia on striatal and amygdala neurons in BBS mice. Interestingly, these mice display reduced locomotor activity and adult onset obesity; phenotypes that are consistent with defective D1 signaling. We hypothesize that trafficking of GPCRs into and out of cilia coordinates receptor signaling and disruption of ciliary localization alters the regulation o GPCR signaling. The objectives of this application are to determine the effects of D1 ciliary accumulation and loss of D1 ciliary localization on D1 expression, trafficking and signaling. The outcomes of this work are expected to fundamentally advance our understanding of the role of cilia in the regulation of D1 signaling. These studies will provide the critical insights into ciliry signaling that are needed to establish the importance of GPCR localization in neuronal cilia throughout the brain.