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Novel aspects of the apolipoprotein-E receptor family： regulation and functional role of their proteolytic processing

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Frontiers in biology 2012年第2期7卷 113-143页

作者： Jorge A. LARIOS Maria-Paz MARZOLO Laboratorio de Trafico lntracelular y Senalizacion Departamento de Biologla Celular y Molecular Pontifieia Universidad Catolica de Chile Alameda # 340 Santiago Chile millenium nucleus in regenerative biology （minreb） Facultad de Ciencias Biol6gieas Pontificia Universidad Catolica de Chile Alameda # 340 Santiago Chile

Studies related to the functional and regulatory aspects of proteolytic processing are of interest to cell biologists, developmental biologists and investigators who work on human diseases. Much of what is known about this topic derives from the study of the proteolytic processing of the amyloid precursor protein （APP）, which is involved in the pathology of Alzheimer＇s disease, and of the Notch protein and its Delta ligand, which play roles during embryonic development and in biologic processes in the adult. The proteolytic processing of plasma membrane receptor proteins is under the control of different enzymes that are responsible for releasing the ectodomain into the extracellular environment, where it has the potential to function as a signaling molecule and/or regulate the availability of the receptor＇s ligand. Following shedding of the ectodomain, the y-secretase enzymatic complex cleaves the transmembrane domain and releases the cytoplasmic domain （ICD） of the receptor. The ICD can function in the cytoplasm and/or at the nucleus. Members of the low-density lipoprotein receptor （LDLR） family are cndocytic-signaling proteins that perform a wide variety of physiologic functions during development and in the adult life. In addition these receptors have been implicated in a variety of diseases in adults. The prototypic receptor for this family of proteins is the LDLR itself. Besides their binding to apolipoproteins, these receptors bind many ligands that are destined for internalization and degradation. Some ligands have signaling properties. The proteolytic processing of certain members of the LDLR family not only controls receptor availability at the cell surface but also has functional consequences that amplify the spectrum of roles that these receptors perform. In addition, many complex regulatory mechanisms control the proteolytie processing of these receptors.

关键词： ADAM APP LDLR LRP metalloproteinase secretase

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Endocytic Trafficking towards the Vacuole Plays a Key Role in the Auxin Receptor SCF^TIR-Independent Mechanism of Lateral Root Formation in A. thaliana

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Molecular Plant 2012年第6期5卷 1195-1209页

作者： Patricio Perez-Henrique Natasha V. Raikhel Lorena Norambuena Plant Molecular biology Laboratory Department of Biology Faculty of Sciences University of Chile Santiago Chile millenium nucleus in Plant Cell Biotechnology Chile Center for Plant Cell biology and Department of Botany and Plant Sciences University of California Riverside CA 92521 USA

Plants＇ developmental plasticity plays a pivotal role in responding to environmental conditions. One of the most plastic plant organs is the root system. Different environmental stimuli such as nutrients and water deficiency may induce lateral root formation to compensate for a low level of water and/or nutrients. It has been shown that the hor- mone auxin tunes lateral root development and components for its signaling pathway have been identified. Using chemi- cal biology, we discovered an Arabidopsis thaliana lateral root formation mechanism that is independent of the auxin receptor SCFTM. The bioactive compound Sortin2 increased lateral root occurrence by acting upstream from the morpho- logical marker of lateral root primordium formation, the mitotic activity. The compound did not display auxin activity. At the cellular level, Sortin2 accelerated endosomal trafficking, resulting in increased trafficking of plasma membrane recy- cling proteins to the vacuole. Sortin2 affected Late endosome/PVC/MVB trafficking and morphology. Combining Sortin2 with well-known drugs showed that endocytic trafficking of Late E/PVC/MVB towards the vacuole is pivotal for Sortin2- induced SCFTm-independent lateral root initiation. Our results revealed a distinctive role for endosomal trafficking in the promotion of lateral root formation via a process that does not rely on the auxin receptor complex SCFTM.

关键词： lateral root development endocytic trafficking Sortin2 endosomes Arabidopsis.

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Bursting the unfolded protein response accelerates axonal regeneration

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Neural Regeneration Research 2016年第6期11卷 892-893页

作者： Maritza Onate Geroscience Center for Brain Health and Metabolism Santiago Chile Center for Integrative biology Universidad Mayor Santiago Chile Biomedical Neuroscience Institute Faculty of Medicine University of Chile Santiago Chile Program of Cellular and Molecular biology Institute of Biomedical Sciences Center for Molecular Studies of the Cell University of ChileSantiago Chile millenium nucleus for regenerative biology Santiago Chile Buck Institute for Research on Aging Novato CA 94945 USA Department of Immunology and Infectious Diseases Harvard School of Public Health Boston MA USA

Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is *** pathological state are are associated with weakness,pain,and loss of motor and sensory *** than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the *** to peripheral nerves results in disabling loss of sensory and motor func-

关键词： axonal regeneration sensory nerves prognosis weakness classified myelin glial neuronal

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A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang Juan Carlos Izpisua Belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and regenerative Medicine Beijing 100101China Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

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Brain circuits for retching-like behavior

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National Science Review 2024年第1期11卷 145-160页

作者： Lifang Huo Zhimin Ye Meiling Liu Ziqing He Meizhu Huang Dapeng Li Qian Wu Qian Wang Xiaoqun Wang Peng Cao Ji Dong Congping Shang School of Basic Medical Sciences Guangzhou National Laboratory The Fifth Afflliated Hospital Guangzhou Medical University Bioland Laboratory (Guangzhou regenerative Medicine and Health Guangdong Laboratory) Department of Neurobiology School of Basic Medical Sciences Beijing Key Laboratory of Neural Regeneration and Repair Advanced Innovation Center for Human Brain Protection Capital Medical University State Key Laboratory of Cognitive Neuroscience and Learning IDG/McGovern Institute for Brain Research Beijing Normal University Changping Life Science Laboratory National Institute of Biological Sciences

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract(NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive(Calb1+) NTS neurons that are molecularly distinct from Tac1+*** Calb1+neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by Bacillus Cereus. Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

关键词： vomiting nausea nucleus of the solitary tract Calbindin1 neural circuits

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Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

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Protein & Cell 2024年第6期15卷 441-459页

作者： Feifei Liu Yi Lu Xuebao Wang Shuhui Sun Huize Pan Min Wang Zehua Wang Weiqi Zhang Shuai Ma Guoqiang Sun Qun Chu Si Wang Jing Qu Guang-Hui Liu State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Sports Medicine Department Beijing Jishuitan HospitalCapital Medical UniversityBeijing 100035China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and regenerative Medicine Beijing 100101China National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Division of Life Sciences and Medicine School of Life SciencesUniversity of Science and Technology of ChinaHefei 230001China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China The Fifth People’s Hospital of Chongqing Chongqing 400062China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China

The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint ***,the mechanism underlying human synovial aging remains poorly ***,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged *** delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two subsets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged ***,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue *** particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differentially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged *** human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged *** data indicate an important role of FOXO1 in the regulation of human synovial ***,our study improves our understanding of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

关键词： FOXO1 degeneration inflammation

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Differential regulation of H3S10 phosphorylation, mitosis progression and cell fate by Aurora Kinase B and C in mouse preimplantation embryos

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Protein & Cell 2017年第9期8卷 662-674页

作者： Wenzhi Li Peizhe Wang Bingjie Zhang Jing Zhang Jia Ming Wei Xie Jie Na Center for Stem Cell biology and regenerative Medicine School of Medicine Tsinghua University Beijing 100084 China Center for Stem Cell biology and regenerative Medicine MOE Key Laboratory of Bioinformatics THU-PKU Center for LifeSciences School of Life Sciences Tsinghua University Beijing 100084 China

Coordination of cell division and cell fate is crucial for the successful development of mammalian early embryos. Aurora kinases are evolutionarily conserved serine/threonine kinases and key regulators of mitosis. Aurora kinase B （AurkB） is ubiquitously expressed while Aurora kinase C （AurkC） is specifically expressed in gametes and preimplantation embryos. We found that increasing AurkC level in one blastomere of the 2-cell embryo accelerated cell division and decreasing AurkC level slowed down mitosis. Changing AurkB level had the opposite effect. The kinase domains of AurkB and AurkC were responsible for their different ability to phosphorylate Histone H3 Serine 10 （H3S10P） and regulate metaphase timing. Using an Oct4-photoactivat- able GFP fusion protein （Oct4-paGFP） and fluorescence decay after photoactivation assay, we found that AurkB overexpression reduced Oct4 retention in the nucleus. Finally, we show that blastomeres with higher AurkC level elevated pluripotency gene expression, which were inclined to enter the inner cell mass lineage and subsequently contributed to the embryo proper. Collectively, our results are the first demonstration that the activity of mitotic kinases can influence cell fate decisions in mammalian preimplantation embryos and have important implications to assisted reproduction.

关键词： Aurora kinase mouse preimplantation embryo cell fate development mitosis

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Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

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Protein & Cell 2024年第8期15卷 612-632页

作者： Qinchao Hu Bin Zhang Yaobin Jing Shuai Ma Lei Hu jingyi Li Yandong Zheng Zijuan Xin Jianmin Peng Si Wang Bin Cheng Jing Qu Weiqi zhang Guang-Hui Liu Songlin Wang State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Hospital of Stomatology Guanghua School of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhou 510060China Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Beijing Laboratory of Oral Health and Beijing Stomatological HospitalCapital Medical UniversityBeijing 100050China Department of Biochemistry and Molecular biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Key Laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and regenerative Medicine Beijing 100101China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center Intermational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuan Wu HospitalCapital Medical UniversityBeijing 100053China Intemational Center for Aging and Cancer Hainan Medical UniversityHaikou 571199China Aging Biomarker Consortium Beijing 100101China

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis,a worldwide prevalent inflammatory ***,a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still ***,we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging,by which a panel of cell type-specific signatures were *** cells were identified as the most affected cell types by aging in the *** analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis,which declined during aging in epithelial cells,especially in basal *** decline of YAP activity during aging was confrmed in the human gingival tissues,and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation *** work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases,with the ultimate goal of advancing periodontal health and promoting healthy aging.

关键词： single-nucleus RNA-sequencing primate gingiva aging YAP

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Development of the nervous system in mouse liver

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World Journal of Hepatology 2022年第2期14卷 386-399页

作者： Naoto Koike Tomomi Tadokoro Yasuharu Ueno Satoshi Okamoto Tatsuya Kobayashi Soichiro Murata Hideki Taniguchi Department of Surgery Seirei Sakura Citizen HospitalSakura 285-8765ChibaJapan Department of regenerative Medicine Yokohama City University Graduate School of MedicineYokohama 236-0004KanagawaJapan Division of regenerative Medicine Center for Stem Cell Biology and Regenerative MedicineThe Institute of Medical ScienceThe University of TokyoTokyo 108-8639Japan

BACKGROUND The role of the hepatic nervous system in liver development remains *** previously created functional human micro-hepatic tissue in mice by co-culturing human hepatic endodermal cells with endothelial and mesenchymal ***,they lacked Glisson’s sheath[the portal tract(PT)].The PT consists of branches of the hepatic artery(HA),portal vein,and intrahepatic bile duct(IHBD),collectively called the portal triad,together with autonomic *** To evaluate the development of the mouse hepatic nervous network in the PT using *** Liver samples from C57BL/6J mice were harvested at different developmental time periods,from embryonic day(E)10.5 to postnatal day(P)*** sections of the surface cut through the hepatic hilus were examined using protein gene product 9.5(PGP9.5)and cytokeratin 19(CK19)antibodies,markers of nerve fibers(NFs),and biliary epithelial cells(BECs),*** numbers of NFs and IHBDs were separately counted in a PT around the hepatic hilus(center)and the peripheral area(periphery)of the liver,comparing the average values between the center and the periphery at each developmental ***-IHBD and NF-HA contacts in a PT were counted,and their relationship was *** high mobility group-box gene 9(SOX9),another BEC marker;hepatocyte nuclear factor 4α(HNF4α),a marker of hepatocytes;and Jagged-1,a Notch ligand,were also immunostained to observe the PT *** HNF4αwas expressed in the nucleus,and Jagged-1 was diffusely positive in the primitive liver at E10.5;however,the PGP9.5 and CK19 were negative in the fetal ***9-positive cells were scattered in the periportal area in the liver at *** Jagged-1 was mainly expressed in the periportal tissue,and the number of SOX9-positive cells increased at ***9-positive cells constructed the ductal plate and primitive IHBDs mainly at the center,and SOX-9-positive IHBDs partly acquired CK19 positivity at the same perio

关键词： Nervous system Liver Portal tract Hepatic artery Immunohistochemistry Tissue engineering

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Generating a reporter mouse line marking medium spiny neurons in the developing striatum driven by Arpp21 cis-regulatory elements

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Journal of Genetics and Genomics 2018年第12期45卷 673-676页

作者： Pan Chen Xiangbin Ruan Yongqiang Chen Shilong Chu Kunlun Mo Chao Wu Wei Liu Bin Yin Junjie Zhou Liang Li Lin Hou Jiangang Yuan Boqin Qiang Jiekai Chen Pengcheng Shu Xiaozhong Peng State Key Laboratory of Medical Molecular biology Department of Molecular Biology and Biochemistry Institute of Basic Medical Sciences Medical Primate Research Center Neuroscience CenterChinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College CAS Key Laboratory of regenerative biology South China Institute for Stem Cell Biology and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Department of Anatomy and Histology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College Institute of Medical biology Chinese Academy of Medical Sciences Chinese Academy of Medical Science and Peking Union Medical College

The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.

关键词： BAC Generating a reporter mouse line marking medium spiny neurons in the developing striatum driven by Arpp21 cis-regulatory elements cis

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