Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway.We have previously reported that cerebral overexpres-sion of furin promotes cognitive functions in...Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway.We have previously reported that cerebral overexpres-sion of furin promotes cognitive functions in mice.Here,by generating the brain-specific furin conditional knockout(ckO)mice,we investigated the role of furin in brain development.We found that furin deficiency caused early death and growth retardation.Magnetic resonance im-aging showed severe hydrocephalus.In the brain of furin cko mice,impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expres-sion of RAB28,a ciliary vesicle protein.In line with the widespread neuronal loss,ependymal cell layers were damaged.Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice;and astrocyte overgrowth was accompanied by the reduced expression of sox9,indicating a disrupted differ-entiation into ependymal cells.Together,whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis,dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin ckO mice.The structural and mo-lecular alterations provided a clue for further studying the potential mechanisms of furin.展开更多
Nuclear distribution gene C （NudC） was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mamma- lian homolog is Lissencephaly 1 （Lisl）. NudC is conserved from fungi to mammals. Vertebrate...Nuclear distribution gene C （NudC） was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mamma- lian homolog is Lissencephaly 1 （Lisl）. NudC is conserved from fungi to mammals. Vertebrate NudC has three homologs： NudC, NudC-like protein （NudCL）, and NudC-like protein 2 （NudCL2）. All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 （Hsp90）. Our group and the others found that NudC homologs were involved in cell cycle regulation by stabilizing the components of the LIS l/dynein complex. Additionally, NudC plays important roles in cell migration, ciliogenesis, thrombopoiesis, and the in- flammatory response. It has been reported that NudCL is essential for the stability of the dynein intermediate chain and cilio- genesis via its interaction with the dynein 2 complex. Our data showed that NudCL2 regulates the LISl/dynein pathway by stabilizing LIS 1 with Hsp90 chaperone. The fourth distantly related member of the NudC family, CML66, a tumor-associated antigen in human leukemia, contains a p23 domain and appears to promote oncogenesis by regulating the IGF-1R-MAPK sig- naling pathway. In this review, we summarize our current knowledge of the NudC family and highlight its potential clinical relevance.展开更多
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 adapt...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.展开更多
Cilia are microtubule-based organelles projected from most eukaryotic cell surfaces performing cell motility and signaling.Several previously recognized non-ciliary proteins play crucial roles in cilium formation and ...Cilia are microtubule-based organelles projected from most eukaryotic cell surfaces performing cell motility and signaling.Several previously recognized non-ciliary proteins play crucial roles in cilium formation and function.Here,we provide additional evidence that the Caenorhabditis elegans RNA splicing factor PRP-8/PRPF8 regulates ciliogen-esis and regeneration from the ciliary base.Live imaging of GFP knock-in animals reveals that the endogenous PRP-8 localizes in the nuclei and the ciliary base.A weak loss-of-function allele of prp-8 affects ciliary structure but with little impact on RNA splicing.Conditional degradation of PRP-8 within ciliated sensory neurons showed its direct and spe-cific roles in cilium formation.Notably,the penetrance of ciliary defects correlates with the reduction of PRP-8 at the ciliary base but not nuclei,and sensory neurons regenerated cilia accompanying PRP-8 recovery from the ciliary base rather than the nuclei.We suggest that PRP-8 at the ciliary base contributes to cilium formation and regeneration.展开更多
One of the most widespread cellular organelles in nature is cilium,which is found in many unicellular and multicellular organisms.Formerly thought to be a mostly vestigial organelle,the cilium has been discovered in t...One of the most widespread cellular organelles in nature is cilium,which is found in many unicellular and multicellular organisms.Formerly thought to be a mostly vestigial organelle,the cilium has been discovered in the past several decades to play critical motile and sensory roles involved in normal organogenesis during development.The role of cilia has also been implicated in an ever increasing array of seemingly unrelated human diseases,including blindness,kidney cysts,neural tube defects and obesity.In this article we review some of the recent developments in research on cilia,and how defects in ciliogenesis and function can give rise to developmental disorders and disease.展开更多
The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate cells.The motility of cilia is necessary for various developmental and physiological processes.Phosphoinositides(PIs...The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate cells.The motility of cilia is necessary for various developmental and physiological processes.Phosphoinositides(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and disassembly.As an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase isoform.However,its potential roles in organ development remain to be characterized.To investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 technique.The homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other organs.Moreover,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb mutants.At the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 kb.In addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb mutants.Taken together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.展开更多
纤毛内转运蛋白20(intraflagellar transport protein 20,IFT20)是细胞纤毛内转运蛋白B类中的一种,定位于高尔基体,在纤毛内蛋白转运、纤毛组装和维持纤毛正常形态等多种生理功能的调节中具有关键性作用。IFT20的异常表达与肿瘤、多囊...纤毛内转运蛋白20(intraflagellar transport protein 20,IFT20)是细胞纤毛内转运蛋白B类中的一种,定位于高尔基体,在纤毛内蛋白转运、纤毛组装和维持纤毛正常形态等多种生理功能的调节中具有关键性作用。IFT20的异常表达与肿瘤、多囊肾、免疫紊乱等多种疾病的发生有关,可能是一些重大疾病防治的分子靶点。展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81971030,82271461 to GJ Chen).
文摘Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway.We have previously reported that cerebral overexpres-sion of furin promotes cognitive functions in mice.Here,by generating the brain-specific furin conditional knockout(ckO)mice,we investigated the role of furin in brain development.We found that furin deficiency caused early death and growth retardation.Magnetic resonance im-aging showed severe hydrocephalus.In the brain of furin cko mice,impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expres-sion of RAB28,a ciliary vesicle protein.In line with the widespread neuronal loss,ependymal cell layers were damaged.Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice;and astrocyte overgrowth was accompanied by the reduced expression of sox9,indicating a disrupted differ-entiation into ependymal cells.Together,whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis,dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin ckO mice.The structural and mo-lecular alterations provided a clue for further studying the potential mechanisms of furin.
基金supported by the Ministry of Science and Technology of China (2012CB945004, 2013CB945603)Natural Scientific Foundation of China (31125017, 31190063, 31100975, 31301149, 31471259)the 111 Project (B13026)
文摘Nuclear distribution gene C （NudC） was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mamma- lian homolog is Lissencephaly 1 （Lisl）. NudC is conserved from fungi to mammals. Vertebrate NudC has three homologs： NudC, NudC-like protein （NudCL）, and NudC-like protein 2 （NudCL2）. All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 （Hsp90）. Our group and the others found that NudC homologs were involved in cell cycle regulation by stabilizing the components of the LIS l/dynein complex. Additionally, NudC plays important roles in cell migration, ciliogenesis, thrombopoiesis, and the in- flammatory response. It has been reported that NudCL is essential for the stability of the dynein intermediate chain and cilio- genesis via its interaction with the dynein 2 complex. Our data showed that NudCL2 regulates the LISl/dynein pathway by stabilizing LIS 1 with Hsp90 chaperone. The fourth distantly related member of the NudC family, CML66, a tumor-associated antigen in human leukemia, contains a p23 domain and appears to promote oncogenesis by regulating the IGF-1R-MAPK sig- naling pathway. In this review, we summarize our current knowledge of the NudC family and highlight its potential clinical relevance.
基金Supported by Project of Health and Family Planning Commission of Jiangxi Province(2014A027)Scientific and Technological Project of Jiangxi Provincial Department of Education(GJJ160843)"Study on Weight-reducing Effect and Mechanism of Coix Seed"
文摘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.
基金This work was supported by the National Natural Science Foundation of China(grants 31991190,31730052,31525015,31861143042,31561130153,31671444,31871352)the National Key R&D Program of China(2017YFA0503501,2019YFA0508401,and 2017YFA0102900)。
文摘Cilia are microtubule-based organelles projected from most eukaryotic cell surfaces performing cell motility and signaling.Several previously recognized non-ciliary proteins play crucial roles in cilium formation and function.Here,we provide additional evidence that the Caenorhabditis elegans RNA splicing factor PRP-8/PRPF8 regulates ciliogen-esis and regeneration from the ciliary base.Live imaging of GFP knock-in animals reveals that the endogenous PRP-8 localizes in the nuclei and the ciliary base.A weak loss-of-function allele of prp-8 affects ciliary structure but with little impact on RNA splicing.Conditional degradation of PRP-8 within ciliated sensory neurons showed its direct and spe-cific roles in cilium formation.Notably,the penetrance of ciliary defects correlates with the reduction of PRP-8 at the ciliary base but not nuclei,and sensory neurons regenerated cilia accompanying PRP-8 recovery from the ciliary base rather than the nuclei.We suggest that PRP-8 at the ciliary base contributes to cilium formation and regeneration.
文摘One of the most widespread cellular organelles in nature is cilium,which is found in many unicellular and multicellular organisms.Formerly thought to be a mostly vestigial organelle,the cilium has been discovered in the past several decades to play critical motile and sensory roles involved in normal organogenesis during development.The role of cilia has also been implicated in an ever increasing array of seemingly unrelated human diseases,including blindness,kidney cysts,neural tube defects and obesity.In this article we review some of the recent developments in research on cilia,and how defects in ciliogenesis and function can give rise to developmental disorders and disease.
基金supported by grants from the National Key R&D Program of China(2018YFA0801000)to J.Z.the National Natural Science Foundation of China(31970777,31771628,31601165)Guangdong Natural Science Fund for Distinguished Young Scholars(2017A030306024)to J.Z
文摘The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate cells.The motility of cilia is necessary for various developmental and physiological processes.Phosphoinositides(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and disassembly.As an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase isoform.However,its potential roles in organ development remain to be characterized.To investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 technique.The homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other organs.Moreover,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb mutants.At the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 kb.In addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb mutants.Taken together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.
文摘纤毛内转运蛋白20(intraflagellar transport protein 20,IFT20)是细胞纤毛内转运蛋白B类中的一种,定位于高尔基体,在纤毛内蛋白转运、纤毛组装和维持纤毛正常形态等多种生理功能的调节中具有关键性作用。IFT20的异常表达与肿瘤、多囊肾、免疫紊乱等多种疾病的发生有关,可能是一些重大疾病防治的分子靶点。
