Abstract:
Primary cilia are hair-like structures found on nearly all mammalian cell types, including cells in the developing and adult brain. A diverse set of receptors and signaling proteins localize within cilia to regulate many physiological and developmental pathways, including the Hedgehog (Hh) pathway. Defects in cilia structure, protein localization, and function lead to genetic disorders called ciliopathies, which present with various clinical features that include several neurodevelopmental phenotypes and hyperphagia-associated obesity. Despite their dysfunction being implicated in several disease states, understanding their roles in central nervous system (CNS) development and signaling has proven challenging. We hypothesize that dynamic changes to ciliary protein composition contribute to this challenge and may reflect unrecognized diversity of CNS cilia. The proteins ARL13B and ADCY3 are established markers of cilia in the brain. ARL13B is a regulatory GTPase important for regulating cilia structure, protein trafficking, and Hh signaling, and ADCY3 is a ciliary adenylyl cyclase. Here, we examine the ciliary localization of ARL13B and ADCY3 in the perinatal and adult mouse brain. We define changes in the proportion of cilia enriched for ARL13B and ADCY3 depending on brain region and age. Furthermore, we identify distinct lengths of cilia within specific brain regions of male and female mice. ARL13B+ cilia become relatively rare with age in many brain regions, including the hypothalamic feeding centers, while ADCY3 becomes a prominent cilia marker in the mature adult brain. It is important to understand the endogenous localization patterns of these proteins throughout development and under different physiological conditions as these common cilia markers may be more dynamic than initially expected. Understanding regional- and developmental-associated cilia protein composition signatures and physiological condition cilia dynamic changes in the CNS may reveal the molecular mechanisms associated with the features commonly observed in ciliopathy models and ciliopathies, like obesity and diabetes.
摘要:
初级纤毛是在几乎所有哺乳动物细胞类型上发现的毛发样结构,包括发育中和成年大脑中的细胞。一组不同的受体和信号蛋白位于纤毛内,以调节许多生理和发育途径,包括Hedgehog(Hh)途径。纤毛结构缺陷,蛋白质定位,和功能导致称为纤毛病的遗传性疾病,具有各种临床特征,包括几种神经发育表型和与饮食过度相关的肥胖。尽管它们的功能障碍与几种疾病状态有关,了解它们在中枢神经系统(CNS)发育和信号传导中的作用已被证明具有挑战性。我们假设纤毛蛋白组成的动态变化促成了这一挑战,并且可能反映了中枢神经系统纤毛的未被识别的多样性。蛋白质ARL13B和ADCY3是脑中纤毛的确定标记。ARL13B是调节纤毛结构的重要调节GTP酶,蛋白质贩运,和Hh信号,ADCY3是纤毛腺苷酸环化酶。这里,我们检查了围产期和成年小鼠大脑中ARL13B和ADCY3的纤毛定位。我们根据大脑区域和年龄定义了富含ARL13B和ADCY3的纤毛比例的变化。此外,我们在雄性和雌性小鼠的特定脑区鉴定出不同长度的纤毛。随着年龄的增长,ARL13B+纤毛在许多大脑区域变得相对罕见,包括下丘脑喂养中心,而ADCY3成为成熟成人大脑中突出的纤毛标记。重要的是要了解这些蛋白质在整个发育过程中和在不同生理条件下的内源性定位模式,因为这些常见的纤毛标记可能比最初预期的更动态。了解区域和发育相关的纤毛蛋白质组成特征和中枢神经系统的生理状况纤毛动态变化可能揭示与纤毛模型和纤毛病中常见特征相关的分子机制。比如肥胖和糖尿病.