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Role of lipids in the control of autophagy and primary cilium signaling in neurons

Neural Regeneration Research 2024年第2期19卷 264-271页

作者： María Paz Hernández-Cáceres Daniela Pinto-Nuñez Patricia Rivera Paulina Burgos Francisco Díaz-Castro Alfredo Criollo Maria Jose Yañez Eugenia Morselli Instituto de Investigación en Ciencias Odontológicas(ICOD) Facultad de OdontologíaUniversidad de ChileSantiagoChile Department of Basic Sciences Faculty of Medicine and ScienceUniversidad San SebastiánSantiagoChile Physiology Department Faculty of Biological SciencesPontificia Universidad Católica de ChileSantiagoChile Advanced Center for Chronic Diseases(ACCDiS) Facultad de Ciencias Químicas y Farmacéuticas&Facultad de MedicinaUniversidad de ChileSantiagoChile Autophagy Research Center SantiagoChile

The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human *** neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely *** this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in *** we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.

关键词： autophagic flux cholesterol fatty acids GPCR lysosomal storage diseases neurons NPC1 phosphoinositides primary cilium

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Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium

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Science China(Life Sciences) 2022年第3期65卷 500-514页

作者： Eva Cai Jingyi Zhang Xuecai Ge Department of Molecular and Cell Biology School of Natural SciencesUniversity of CaliforniaMerced CA 95340USA

The Hedgehog(Hh)signaling is one of the essential signaling pathways during embryogenesis and in *** signal transduction relies on primary cilium,a specialized cell surface organelle viewed as the hub of cell *** kinase A(PKA)has been recognized as a potent negative regulator of the Hh pathway,raising the question of how such a ubiquitous kinase specifically regulates one signaling *** reviewed recent genetic,molecular and biochemical studies that have advanced our mechanistic understanding of PKA’s role in Hh signaling in vertebrates,focusing on the compartmentalized PKA at the centrosome and in the primary *** outlined the recently developed genetic and optical tools that can be harvested to study PKA activities during the course of Hh signal transduction.

关键词： Hedgehog signaling protein kinase A(PKA) primary cilium centrosome compartmentalized cell signaling

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Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine?

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World Journal of Stem Cells 2021年第9期13卷 1177-1196页

作者： Andreas Goutas Varvara Trachana Department of Biology Faculty of MedicineUniversity of ThessalyLarisa 41500BiopolisGreece

At the core of regenerative medicine lies the expectation of repair or replacementof damaged tissues or whole organs. Donor scarcity and transplant rejection aremajor obstacles, and exactly the obstacles that stem cell􀀀based therapy promisesto overcome. These therapies demand a comprehensive understanding of theasymmetric division of stem cells, i.e. their ability to produce cells with identicalpotency or differentiated cells. It is believed that with better understanding,researchers will be able to direct stem cell differentiation. Here, we describeextraordinary advances in manipulating stem cell fate that show that we need tofocus on the centrosome and the centrosome-derived primary cilium. This beliefcomes from the fact that this organelle is the vehicle that coordinates theasymmetric division of stem cells. This is supported by studies that report thesignificant role of the centrosome/cilium in orchestrating signaling pathways thatdictate stem cell fate. We anticipate that there is sufficient evidence to place thisorganelle at the center of efforts that will shape the future of regenerativemedicine.

关键词： Centrosome primary cilium Asymmetry Self-renewal Differentiation Stemness

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The roles and activation of endocardial Notch signaling in heart regeneration

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Cell Regeneration 2021年第1期10卷 27-34页

作者： Huicong Li Cheng Chang Xueyu Li Ruilin Zhang School of Life Sciences Fudan UniversityShanghaiChina School of Basic Medical Sciences Wuhan UniversityWuhanChina

As a highly conserved signaling pathway in metazoans,the Notch pathway plays important roles in embryonic development and tissue ***,cardiac injury and regeneration have become an increasingly popular topic for biomedical research,and Notch signaling has been shown to exert crucial functions during heart regeneration as *** this review,we briefly summarize the molecular functions of the endocardial Notch pathway in several cardiac injury and stress *** there is an increase in appreciating the importance of endocardial Notch signaling in heart regeneration,the mechanism of its activation is not fully *** review highlights recent findings on the activation of the endocardial Notch pathway by hemodynamic blood flow change in larval zebrafish ventricle after partial ablation,a process involving primary cilia,mechanosensitive ion channel Trpv4 and mechanosensitive transcription factor Klf2.

关键词： Heart regeneration Notch signaling Hemodynamic alteration klf2 primary cilium Ion channel

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Mechanosensation of osteocyte with collagen hillocks and primary cilia under pressure and electric field stimulation

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Acta Mechanica Sinica 2022年第3期38卷 172-186,I0004页

作者： Yan Wang Chaoxin Li Hao Dong Jianhao Yu Yang Yan Xiaogang Wu Yanqin Wang Pengcui Li Xiaochun Wei Weiyi Chen College of Biomedical Engineering Taiyuan University of TechnologyTaiyuan 030024China Shanxi Provincial Key Laboratory for Repair of Bone and Soft Tissue Injury Taiyuan 030001China

Mechanosensors are the most important organelles for osteocytes to perceive the changes of surrounding mechanical *** evaluate the biomechanical effectiveness of collagen hillock,cell process and primary·cilium in lacunar-canalicular system(LCS),we developed pressure-electricity-structure interaction models by using the COMSOL Multiphysics software to characterize the deformation of collagen hillocks-and primary cilium-based mechanosensors in osteocyte under fluid flow and electric field *** mechanical signals(pore pressure,fluid velocity,stress,deformation)were analyzed in *** effects of changes in the elastic modulus of collagen hillocks,the number and location of cell processes,the length and location of primary cilia on the mechanosensitivity and the overall poroelastic responses of osteocytes were *** models predict that the presence of primary cilium and collagen hillocks resulted in significant stress amplifications(one and two orders of magnitude larger than osteocyte body)on the *** growth of cell process along the long axis could stimulate osteocyte to a higher level than along the short *** Mises stress of the basal body of primary cilia near the top of osteocyte is 8 Pa greater than that near the ***,the presence of collagen hillocks and primary cilium does not affect the mechanical signal of the whole osteocyte *** established model can be used for studying the mechanism of bone mechanotransduction at the multiscale level.

关键词： Osteocyte Cell Process primary cilium Collagen Hillock Finite Element

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Ciliotherapy： a novel intervention in polycystic kidney disease

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Journal of Geriatric Cardiology 2014年第1期11卷 63-73页

作者： Sarmed H. Kathem Ashraf M. Mohieldin Shakila Abdul-Majeed Sajida H. Ismail Qaiss H. Altaei Ibrahim K. Alshimmari Mohanned M. Alsaidi Hussein Khammas Andromeda M. Nauli Bina Joe Surya M. Nauli Centerfor Hypertension and Personalized Medicine University of Toledo Health Science Building Room 312 3000 Arlington Ave. Toledo OH 43614 USA Department of Pharmacology University of Toledo Health Education Building Room 274 3000 Arlington Ave. Toledo OH 43614 USA College of Pharmacy University of Baghdad Bab-Almoadhum 14026 Baghdad Iraq Kidney Disease and Transplant Center Medical City Complex Bab-Almoadhum 14026 Baghdad Iraq Alkadhumia Academic Hospital Bab-Almoadhum 14026 Baghdad Iraq pharmaceutical & Biomedical Sciences California Northstate University 10811 International Drive Rancho Cordova CA 95670 USA

Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.

关键词： primary cilium Blood pressure Mechanosensor Mechanotransduction Chemosensor Fluid-shear stress

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Potential Application of TCM Sophoridine in Regulating Intensity of Autophagy to Treat PKD

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Medicinal Plant 2018年第4期9卷 97-101,106页

作者： Guangqiang MA Yan LIN Hanfeng CUI Qinglong SHU Hongjiao WAN Jiangxi University of Traditional Chinese Medicine

Nearly all cells have primary cilia( PC) composed of microtubules,primary cilia mainly functioning as sensing various signals of the environment and coordinating intracellular signaling pathways. Autophagy is an adaptive response of cells to environmental stress such as starvation/inflammation and infection. Many ciliopathies may induce autophagy. Polycystic kidney disease( PKD) is the most common ciliopathy,with the incidence of 1/500 to 1/1 000 in the world. A typical symptom of the PKD is the chronic development of multiple renal cysts that may eventually develop into advanced kidney disease. Sophoridine is an alkaloid extracted from the traditional Chinese medicinal plant Sophora alopecuroides L. It is a new antitumor drug which has the function of inducing cell autophagy. This paper mainly discussed the possibility of treating PKD through sophoridine inducing autophagy.

关键词： Autophagy Ciliogenesis Ciliopathy primary cilium

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The research on the function of C21ORF2 gene in photoreceptor

The research on the function of C21ORF2 gene in photorecepto...

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第一届中国临床分子诊断大会

作者：任芝霖四川省人民医院·四川省医学科学院

Purpose: Recently, two RNAi-based functional screening for cilium-associated genes have both identified an LRR-containing protein, C21ORF2. The subsequent genetic studies demonstrated that C21ORF2 mutations cause both syndromic and non-syndromic forms of retinal ciliopathy with a variable spectrum of skeletal involvement. The affected patients all share severe cone-rod dystrophy in early childhood. In photoreceptor, C21ORF2 protein was found to localize at the transition zone（TZ）, but its function remains unknown. Our study is aim to identify the function of C21ORF2 gene in photoreceptors and to reveal the pathogenesis of related retinal ciliopathy caused by C21ORF2 gene mutations. Methods: We first examined location of C21ORF2 in mouse photoreceptors by western blotting and immunocytochemistry. To study function of C21ORF2 in vivo, we generated three constructs encoding mouse wild type C21ORF2-GFP, retinal ciliopathy causative mutants C21ORF2（G218 C）-GFP and C21ORF2（103 delA）-GFP. They were transfected into the ciliated cells, IMCD3 and RPE9. And then we analyzed their expression level and subcellular localization of C21ORF2 wild type and mutants by western blotting and immunocytochemistry. Results: Mouse C21orf2 gene is expressed in both mouse retina and ciliated cells. Its subcellular localization is at the connecting cilium of mouse photoreceptors. In the transfected ciliated cells, wild type C21 ORF2-GFP are expressed, and specifically localized around the transition zone of cilia. The expression level of C21 ORF2（G218C）-GFP mutant is decreased compared to that of C21ORF2-GFP in the transfected ciliated cells, while C21ORF2（103 delA）-GFP mutant shows no expression. The subcellular localization of C21ORF2（G218 C）-GFP in the ciliated cells is under studying. Conclusion: Our study indicates that C21ORF2 is ciliary protein specifically localized at the photoreceptor connecting cilia and ciliary cell transition zone. Retinal ciliopathy-associated mutants C21ORF2（G21

关键词： Photoreceptor primary cilium Retinal ciliopathy C21ORF2

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PCM1 Recruits Plkl to Pericentriolar Matrix to Promote primary Cilia Disassembly before Mitotic Entry

PCM1 Recruits Plkl to Pericentriolar Matrix to Promote Prima...

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细胞—生命的基础——中国细胞生物学学会2013年全国学术大会·武汉

作者： Gang Wang Qiang Chen Xiaoyan Zhang Boyan Zhang Xiaolong Zhuo Junjun Liu Qing Jiang Chuanmao Zhang College of Life Sciences Peking University Department of Biological Sciences California State Polytechnic University

primary cilia,which emanate from the cell surface,exhibit assembly and disassembly dynamics along the progression of cell ***,the mechanism that links ciliary dynamics and cell cycle regulation remains ***,we report that Polo-like kinase 1(Plkl),one of the key cell cycle regulators,which regulate centrosome maturation,bipolar spindle assembly and cytokinesis,acts as a

关键词： Polo-like kinase 1 primary cilium PCM1 HDAC6

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Exploring how primary cilia regulate neuronal activity and brain function

Exploring how primary cilia regulate neuronal activity and b...

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中国神经科学学会第十二届全国学术会议

作者： Nan Wu Xiao-Bing Yuan Wei Gao Shuang-Yi Xie Jing-Yan Jia Key Laboratory of Brain Functional Genomics Ministry of Education/Shanghai Key Laboratory of Brain Functional Genomics East China Normal University

Objective: Most neurons in the brain have a single primary cilium, which is a tiny cell surface protrusion with the accumulation of a group of important receptors, ion channels, and signaling molecules. primary cilia neural stem cell/progenitor cells are known to regulate neuronal genesis by mediating sonic hedgehog signaling during brain development. However, till now the role of cilia in postmitotic neurons remains a mystery. The present study aims to explore whether primary cilium can affect neuronal activity and animal behavior, and clarify the underlying molecular mechanisms. Methods: We took advantage of mouse genetics technology to specifically ablate the cilium of forebrain pyramidal neurons and parvalbumin-positive interneurons, respectively, and clarify its effect on the morphology and electrophysiological properties of neurons, and its impact on animal behavior. Digital Gene Expression Tag Profiling, RT-PCR and Western blotting were further carried out to dissect the signaling mechanism associated with cilium’s function in neurons. Results:（1） Cilia of postmitotic pyramidal neurons in the forebrain were specifically ablated using the Cre-loxp system（Nex-Cre::IFT88 f/f）.（2） The basic locomotion level of KO mice was significantly reduced.（3） The KO mice showed a lower anxiety level compared with wild type littermates.（4） The transcriptional level of DRD1 and DRD2 were both increased in prefrontal ***: Our preliminary results suggest that primary cilium on pyramidal neurons may modulate neuronal activity and animal behavior by regulating the function of dopamine receptors.

关键词： dopamine receptors G protein-coupled receptors primary cilium animal model

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