Publications by authors named "Ruilin Sun"

46 Publications

Longitudinal virological changes and underlying pathogenesis in hospitalized COVID-19 patients in Guangzhou, China.

Sci China Life Sci 2021 Apr 28. Epub 2021 Apr 28.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.

Prolonged viral RNA shedding and recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in coronavirus disease 2019 (COVID-19) patients have been reported. However, the clinical outcome and pathogenesis remain unclear. In this study, we recruited 43 laboratory-confirmed COVID-19 patients. We found that prolonged viral RNA shedding or recurrence mainly occurred in severe/critical patients (P<0.05). The average viral shedding time in severe/critical patients was more than 50 days, and up to 100 days in some patients, after symptom onset. However, chest computed tomography gradually improved and complete absorption occurred when SARS-CoV-2 RT-PCR was still positive, but specific antibodies appeared. Furthermore, the viral shedding time significantly decreased when the A1,430G or C12,473T mutation occurred (P<0.01 and FDR<0.01) and increased when G227A occurred (P<0.05 and FDR<0.05). High IL1R1, IL1R2, and TNFRSF21 expression in the host positively correlated with viral shedding time (P<0.05 and false discovery rate <0.05). Prolonged viral RNA shedding often occurs but may not increase disease damage. Prolonged viral RNA shedding is associated with viral mutations and host factors.
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http://dx.doi.org/10.1007/s11427-020-1921-5DOI Listing
April 2021

The Fungi-specific histone Acetyltransferase Rtt109 mediates morphogenesis, Aflatoxin synthesis and pathogenicity in Aspergillus flavus by acetylating H3K9.

IMA Fungus 2021 Apr 7;12(1). Epub 2021 Apr 7.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Aspergillus flavus is a common saprophytic filamentous fungus that produces the highly toxic natural compound aflatoxin during its growth process. Synthesis of the aflatoxins, which can contaminate food crops causing huge losses to the agricultural economy, is often regulated by epigenetic modification, such as the histone acetyltransferase. In this study, we used Aspergillus flavus as an experimental model to construct the acetyltransferase gene rtt109 knockout strain (△rtt109) and its complementary strain (△rtt109·com) by homologous recombination. The growth of △rtt109 was significantly suppressed compared to the wild type (WT) strain and the △rtt109·com strain. The sclerotium of △rtt109 grew smaller, and the amount of sclerotia generated by △rtt109 was significantly reduced. The number of conidiums of △rtt109 was significantly reduced, especially on the yeast extract sucrose (YES) solid medium. The amount of aflatoxins synthesized by △rtt109 in the PDB liquid medium was significantly decreased We also found that the △rtt109 strain was extremely sensitive to DNA damage stress. Through the maize seed infection experiment, we found that the growth of △rtt109 on the surface of affected corn was largely reduced, and the amount of aerial mycelium decreased significantly, which was consistent with the results on the artificial medium. We further found that H3K9 was the acetylated target of Rtt109 in A. flavus. In conclusion, Rtt109 participated in the growth, conidium formation, sclerotia generation, aflatoxin synthesis, environmental stress response, regulation of infection of A. flavus. The results from this study of rtt109 showed data for acetylation in the regulation of life processes and provided a new thought regarding the prevention and control of A. flavus hazards.
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http://dx.doi.org/10.1186/s43008-021-00060-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025522PMC
April 2021

Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair.

Science 2021 02;371(6532)

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Organ homeostasis is orchestrated by time- and spatially restricted cell proliferation. Studies identifying cells with superior proliferative capacities often rely on the lineage tracing of a subset of cell populations, which introduces a potential selective bias. In this work, we developed a genetic system [proliferation tracer (ProTracer)] by incorporating dual recombinases to seamlessly record the proliferation events of entire cell populations over time in multiple organs. In the mouse liver, ProTracer revealed more hepatocyte proliferation in distinct zones during liver homeostasis, injury repair, and regrowth. Clonal analysis showed that most of the hepatocytes labeled by ProTracer had undergone cell division. By genetically recording proliferation events of entire cell populations, ProTracer enables the unbiased detection of specific cellular compartments with enhanced regenerative capacities.
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http://dx.doi.org/10.1126/science.abc4346DOI Listing
February 2021

A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting.

Cell Stem Cell 2021 Feb 2. Epub 2021 Feb 2.

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address:

The use of the dual recombinase-mediated intersectional genetic approach involving Cre-loxP and Dre-rox has significantly enhanced the precision of in vivo lineage tracing, as well as gene manipulation. However, this approach is limited by the small number of Dre recombinase driver constructs available. Here, we developed more than 70 new intersectional drivers to better target diverse cell lineages. To highlight their applicability, we used these new tools to study the in vivo adipogenic fate of perivascular progenitors, which revealed that PDGFRa but not PDGFRaPDGFRb perivascular cells are the endogenous progenitors of adult adipocytes. In addition to lineage tracing, we used members of this new suite of drivers to more specifically knock out genes in complex tissues, such as white adipocytes and lymphatic vessels, that heretofore cannot be selectively targeted by conventional Cre drivers alone. In summary, these new transgenic tools expand the intersectional genetic approach while enhancing its precision.
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http://dx.doi.org/10.1016/j.stem.2021.01.007DOI Listing
February 2021

The kinetics of viral load and antibodies to SARS-CoV-2.

Clin Microbiol Infect 2020 Dec 6;26(12):1690.e1-1690.e4. Epub 2020 Sep 6.

Guangdong Provincial Centre for Disease Control and Prevention, Guangzhou, China. Electronic address:

Objectives: The aim was to understand persistence of the virus in body fluids the and immune response of an infected host to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), an agent of coronavirus disease 2019 (COVID-19).

Methods: We determined the kinetics of viral load in several body fluids through real time reverse transcription polymerase chain reaction, serum antibodies of IgA, IgG and IgM by enzyme-linked immunosorbent assay and neutralizing antibodies by microneutralization assay in 35 COVID-19 cases from two hospitals in Guangdong, China.

Results: We found higher viral loads and prolonged shedding of virus RNA in severe cases of COVID-19 in nasopharyngeal (1.3 × 10 vs 6.4 × 10, p < 0.05; 7∼8 weeks) and throat (6.9 × 10 vs 2.9 × 10, p < 0.05; 4∼5 weeks), but similar in sputum samples (5.5 × 10 vs 0.9 × 10, p < 0.05; 4∼5 weeks). Viraemia was rarely detected (2.8%, n = 1/35). We detected early seroconversion of IgA and IgG at the first week after illness onset (day 5, 5.7%, n = 2/35). Neutralizing antibodies were produced in the second week, and observed in all 35 included cases after the third week illness onset. The levels of neutralizing antibodies correlated with IgG (r = 0.85, p < 0.05; kappa = 0.85) and IgA (r = 0.64, p < 0.05; kappa = 0.61) in severe, but not mild cases (IgG, r = 0.42, kappa = 0.33; IgA, r = 0.32, kappa = 0.22). No correlation with IgM in either severe (r = 0.17, kappa = 0.06) or mild cases (r = 0.27, kappa = 0.15) was found.

Discussion: We revealed a prolonged shedding of virus RNA in the upper respiratory tract, and evaluated the consistency of production of IgG, IgA, IgM and neutralizing antibodies in COVID-19 cases.
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http://dx.doi.org/10.1016/j.cmi.2020.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474805PMC
December 2020

Expert consensus for diagnosis and treatment using medical thoracoscopy in China.

J Thorac Dis 2020 May;12(5):1799-1810

Department of Respiration, Affiliated Zhongshan Hospital of Guangdong Medical University Zhongshan 524000, China.

Medical thoracoscopy is a commonly used endoscopic technique for the diagnosis and treatment of respiratory diseases. As an invasive technique, it is mainly used for pleural effusions and pleural diseases that cannot be diagnosed by non-invasive methods. It is also of great application in the diagnosis and treatment of certain other diseases. Any technical operation requires special skills. There must be a learning process for mastering these skills. Although internal thoracoscopic surgery is simple, especially for respiratory specialists who have undergone training for thoracentesis or closed drainage, there are discrepancies in thoracoscopic diagnosis and treatment in hospitals in China; furthermore, the surgical methods are not uniform, and some even lead to serious complications. Therefore, the thoracoscopic diagnostic and treatment technology in China needs to be standardized. The Respiratory Professional Committee of the Integrated Medical Branch of the Chinese Medical Doctor Association invited relevant Chinese experts to formulate this standard after several rounds of discussion.
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http://dx.doi.org/10.21037/jtd-19-2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330357PMC
May 2020

STAT3 and AKT signaling pathways mediate oncogenic role of NRSF in hepatocellular carcinoma.

Acta Biochim Biophys Sin (Shanghai) 2020 Oct;52(10):1063-1070

School of Life Science and Technology, Tongji University, Shanghai 200092, China.

Neuron-restrictive silencer factor (NRSF) is a zinc finger protein that acts as a negative transcriptional regulator by recruiting histone deacetylases and other co-factors. It plays a crucial role in nervous system development and is recently reported to be involved in tumorigenesis in a tumor type-dependent manner; however, the role of NRSF in hepatocellular carcinoma (HCC) tumorigenesis remains unclear. Here, we found that NRSF expression was up-regulated in 27 of 49 human HCC tissue samples examined. Additionally, mice with conditional NRSF-knockout in the liver exhibited a higher tolerance against diethylnitrosamine (DEN)-induced acute liver injury and were less sensitive to DEN-induced HCC initiation. Our results showed that silencing NRSF in HepG2 cells using RNAi technology significantly inhibited HepG2 cell proliferation and severely hindered their migration and invasion potentials. Our results demonstrated that NRSF plays a pivotal role in promoting DEN-induced HCC initiation via a mechanism related to the STAT3 and AKT signaling pathways. Thus, NRSF could be a potential therapeutic target for treating human HCC.
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http://dx.doi.org/10.1093/abbs/gmaa069DOI Listing
October 2020

Prolonged Persistence of SARS-CoV-2 RNA in Body Fluids.

Emerg Infect Dis 2020 08 8;26(8):1834-1838. Epub 2020 May 8.

We prospectively assessed 49 coronavirus disease cases in Guangdong, China, to estimate the frequency and duration of detectable severe acute respiratory syndrome coronavirus 2 RNA in human body fluids. The prolonged persistence of virus RNA in various body fluids may guide the clinical diagnosis and prevention of onward virus transmission.
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http://dx.doi.org/10.3201/eid2608.201097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392422PMC
August 2020

Rapid review for the anti-coronavirus effect of remdesivir.

Drug Discov Ther 2020 ;14(2):73-76

Centre of Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.

The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019 (COVID-19). We provided a rapid review to critically assess the potential anti-coronavirus effect of remdesivir on COVID-19 and other coronaviruses based on the most up-to-date evidence. Even though remdesivir was proposed as a promising option for treating COVID-19 based on laboratory experiments and reports from compassionate use, its safety and effect in humans requires high-quality evidence from well-designed and adequately-powered clinical trials for further clarification.
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http://dx.doi.org/10.5582/ddt.2020.01015DOI Listing
May 2020

LncRNA KCNQ1OT1 promotes cell proliferation, migration and invasion via regulating miR-129-5p/JAG1 axis in non-small cell lung cancer.

Cancer Cell Int 2020 1;20:144. Epub 2020 May 1.

Department of Pulmonary and Critical Care Medicine, The Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Rd, Haizhu District, 510000 Guangzhou, China.

Background: Non-small cell lung cancer (NSCLC) is the most deadly cancer worldwide. LncRNA KCNQ1OT1 has been reported to be involved in the progression of various tumors, including NSCLC. However, the precise mechanism of KCNQ1OT1 in NSCLC requires further investigation.

Methods: The expression levels of KCNQ1OT1, miR-129-5p and JAG1 were detected by qRT-PCR or western blot. Kaplan-Meier survival analysis was used to assess the correlation between KCNQ1OT1 expression and the overall survival of NSCLC patients. CCK-8 assay was used to measure cell viability. Cell migration and invasion were detected by transwell assay. The targets of KCNQ1OT1 and miR-129-5p were predicted by bioinformatics, which was confirmed by dual-luciferase reporter assay or pull-down assay.

Results: KCNQ1OT1 expression was significantly enhanced, while miR-129-5p expression was dramatically reduced in NSCLC tissues and cells. Higher KCNQ1OT1 shortened overall survival and was positively associated with tumor stage and lymph node metastasis. KCNQ1OT1 knockdown inhibited proliferation, migration and invasion of NSCLC cells. Inhibition of miR-129-5p attenuated the inhibition of NSCLC cell viability, migration and invasion induced by KCNQ1OT1 knockdown. In addition, JAG1 was confirmed as a target of miR-129-5p. Knockdown of JAG1 reversed the effects of miR-129-5p knockdown on NSCLC progression. KCNQ1OT1 regulated JAG1 expression by sponging miR-129-5p in NSCLC cells.

Conclusion: KCNQ1OT1 induced proliferation, migration and invasion of NSCLC cells by sponging miR-129-5p and regulating JAG1 expression, indicating that KCNQ1OT1 was a therapeutic target for NSCLC.
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http://dx.doi.org/10.1186/s12935-020-01225-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195752PMC
May 2020

Genomic Epidemiology of SARS-CoV-2 in Guangdong Province, China.

Cell 2020 05 30;181(5):997-1003.e9. Epub 2020 Apr 30.

Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 infection and was first reported in central China in December 2019. Extensive molecular surveillance in Guangdong, China's most populous province, during early 2020 resulted in 1,388 reported RNA-positive cases from 1.6 million tests. In order to understand the molecular epidemiology and genetic diversity of SARS-CoV-2 in China, we generated 53 genomes from infected individuals in Guangdong using a combination of metagenomic sequencing and tiling amplicon approaches. Combined epidemiological and phylogenetic analyses indicate multiple independent introductions to Guangdong, although phylogenetic clustering is uncertain because of low virus genetic variation early in the pandemic. Our results illustrate how the timing, size, and duration of putative local transmission chains were constrained by national travel restrictions and by the province's large-scale intensive surveillance and intervention measures. Despite these successes, COVID-19 surveillance in Guangdong is still required, because the number of cases imported from other countries has increased.
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http://dx.doi.org/10.1016/j.cell.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192124PMC
May 2020

Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis.

J Med Virol 2020 Sep 13;92(9):1518-1524. Epub 2020 Apr 13.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

The outbreak of the novel coronavirus disease (COVID-19) quickly spread all over China and to more than 20 other countries. Although the virus (severe acute respiratory syndrome coronavirus [SARS-Cov-2]) nucleic acid real-time polymerase chain reaction (PCR) test has become the standard method for diagnosis of SARS-CoV-2 infection, these real-time PCR test kits have many limitations. In addition, high false-negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify a large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point-of-care lateral flow immunoassay that can detect immunoglobulin M (IgM) and IgG antibodies simultaneously against SARS-CoV-2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID-19 patients and 128 negative patients at eight different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM-IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS-CoV-2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.
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http://dx.doi.org/10.1002/jmv.25727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228300PMC
September 2020

A genetic system for tissue-specific inhibition of cell proliferation.

Development 2020 02 17;147(4). Epub 2020 Feb 17.

The State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China

Cellular proliferation is a basic process during organ development, tissue homeostasis and disease progression. Likewise, after injury typically multiple cell lineages respond to various cues and proliferate to initiate repair and/or remodeling of the injured tissue. Unravelling the specific role of proliferation of one cell type and its lineage in the context of the whole organism during tissue regeneration and/or disease progression would provide valuable information on these processes. Here, we report a new genetic system that allows cell proliferation to be inhibited in a tissue-specific manner. We generated Cre- or Dre-inducible p21-GFP (ip21-GFP) transgenic mice that enable experimentally induced permanent cell cycle arrest of specific cell lineages of interest, while genetically marking these cells. This system allows for the inhibition of pathogenic cell proliferation. We found that cardiac fibroblast proliferation inhibition significantly reduced scar formation, and promoted neovascularization and cardiomyocyte survival. Additionally, we found that inhibition of one type of cell proliferation (namely, hepatocytes) induces the lineage conversion of another type cells (i.e. ductal cells) during tissue regeneration. These results validate the use of ip21-GFP mice as a new genetic tool for cell lineage-specific inhibition of cell proliferation .
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http://dx.doi.org/10.1242/dev.183830DOI Listing
February 2020

Generation of a self-cleaved inducible Cre recombinase for efficient temporal genetic manipulation.

EMBO J 2020 02 14;39(4):e102675. Epub 2020 Jan 14.

Key Laboratory of Regenerative Medicine of Ministry of Education, College of Life Science and Technology, Jinan University, Guangzhou, China.

Site-specific recombinase-mediated genetic technology, such as inducible Cre-loxP recombination (CreER), is widely used for in vivo genetic manipulation with temporal control. The Cre-loxP technology improves our understanding on the in vivo function of specific genes in organ development, tissue regeneration, and disease progression. However, inducible CreER often remains inefficient in gene deletion. In order to improve the efficiency of gene manipulation, we generated a self-cleaved inducible CreER (sCreER) that switches inducible CreER into a constitutively active Cre by itself. We generated endocardial driver Npr3-sCreER and fibroblast driver Col1a2-sCreER, and compared them with conventional Npr3-CreER and Col1a2-CreER, respectively. For easy-to-recombine alleles such as R26-tdTomato, there was no significant difference in recombination efficiency between sCreER and the conventional CreER. However, for alleles that were relatively inert for recombination such as R26-Confetti, R26-LZLT, R26-GFP, or VEGFR2 alleles, sCreER showed a significantly higher efficiency in recombination compared with conventional CreER in endocardial cells or fibroblasts. Compared with conventional CreER, sCreER significantly enhances the efficiency of recombination to induce gene expression or gene deletion, allowing temporal yet effective in vivo genomic modification for studying gene function in specific cell lineages.
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http://dx.doi.org/10.15252/embj.2019102675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024834PMC
February 2020

Betaine/GABA transporter-1 (BGT-1) deficiency in mouse prevents acute liver failure in vivo and hepatocytes apoptosis in vitro.

Biochim Biophys Acta Mol Basis Dis 2020 03 9;1866(3):165634. Epub 2019 Dec 9.

School of Life Science and Technology, Tongji University. Shanghai, China; Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai, China; Joint Laboratory for Model Organism, Shanghai Laboratory Animal Research Center and School of Life Science and Technology, Tongji University. Electronic address:

Betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT-1 or Slc6a12) is a transporter for the neurotransmitter GABA and osmolyte betaine. To date, most studies on BGT-1 have focused on its functions in the nervous system and renal osmotic homeostasis. Despite its dominant distribution in the liver, the function of BGT-1 in hepatic physiology or disease remains unknown. Here, we report that BGT-1 was significantly downregulated in patients with liver failure as well as in mice with experimental acute liver failure (ALF). Furthermore, mice deficient in BGT-1 showed significant resistance to ALF compared with wild type (WT) mice, manifesting as improved survival rate, reduced alanine transaminase/aspartate aminotransferase levels, better histopathological symptoms and fewer apoptotic cells in the liver. Similarly, in primary hepatocytes, BGT-1 deficiency or treatment with a BGT-1 inhibitor, NNC 05-2090, attenuated TNF-α mediated apoptosis. In addition, BGT-1 deficiency or dosing with NNC 05-2090 stimulated the expression of the anti-apoptotic gene, c-Met in the liver, suggesting the involvement of c-Met in the function on hepatocytes of BGT-1 apoptosis. Our findings suggest BGT-1 is a promising candidate drug target to prevent and treat hepatocyte apoptosis related diseases, such as ALF.
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http://dx.doi.org/10.1016/j.bbadis.2019.165634DOI Listing
March 2020

Fate Tracing of Isl1+Cells in Adult Mouse Hearts under Physiological and Exercise Conditions.

Int J Sports Med 2019 Dec 15;40(14):921-930. Epub 2019 Oct 15.

School of Life Science and Technology, Tongji University, Shanghai, China.

Myocardial damage due to dysfunctional myocardium has been increasing, and the prognosis of pharmacological and device-based therapies remain poor. Isl1-expressing cells were thought to be progenitor cells for cardiomyocyte proliferation after specific stimuli. However, the true origin of the proliferating myocardiac cells and the role of Isl1 in adult mammals remain unresolved. In this study, Isl1-CreERT2 knock-in mouse model was constructed using CRISPR/Cas9 technology. Using tamoxifen-inducible Isl1-CreERT/Rosa26R-LacZ system, Isl1cells and their progeny were permanently marked by lacZ-expression. X-gal staining, immunostaining, and quantitative PCR were then used to reveal the fate of Isl1cells under physiological and exercise conditions in mouse hearts from embryonic stage to adulthood. Isl1cells were found to localize to the sinoatrial node, atrioventricular node, cardiac ganglia, aortic arch, and pulmonary roots in adult mice heart. However, they did not act as cardiac progenitor cells under physiological and exercise conditions. Although Isl1cells showed progenitor cell properties in early mouse embryos (E7.5), this ability was lost by E9.5. Furthermore, although the proliferation and regeneration of heart cell was observed in response to exercise, the cells associated were not Isl1 positive.
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http://dx.doi.org/10.1055/a-0961-1458DOI Listing
December 2019

Dnmt3a is required for the tumor stemness of B16 melanoma cells.

Acta Biochim Biophys Sin (Shanghai) 2019 Sep;51(9):945-952

School of Life Science and Technology, Tongji University, Shanghai 200092, China.

The relationship of carcinogenesis and DNA methyltransferases has attracted extensive attention in tumor research. We reported previously that inhibition of de novo DNA methyltransferase 3a (Dnmt3a) in murine B16 melanoma cells significantly suppressed tumor growth and metastasis in xenografted mouse model. Here, we further demonstrated that knockdown of Dnmt3a enhanced the proliferation in anchor-independent conditions of B16 cells, but severely disrupted its multipotent differentiation capacity in vitro. Furthermore, transforming growth factor β1, a key trigger in stem cell differentiation and tumor cell epithelial-mesenchymal transition (EMT), mainly induced apoptosis, but not EMT in Dnmt3a-deficient B16 cells. These data suggested that Dnmt3a is required for maintaining the tumor stemness of B16 cells and it assists B16 cells to escape from death during cell differentiation. Thus it is hypothesized that not only extraordinary self-renewal ability, but also the capacity of multipotent differentiation is necessary for the melanoma tumorigenesis. Inhibition of multipotent differentiation of tumor cells may shed light on the tumor treatment.
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http://dx.doi.org/10.1093/abbs/gmz081DOI Listing
September 2019

Set3 Is Required for Asexual Development, Aflatoxin Biosynthesis, and Fungal Virulence in .

Front Microbiol 2019 29;10:530. Epub 2019 Mar 29.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.

is an opportunistic pathogenic fungus for both plant and animal that produces carcinogenic toxins termed aflatoxins (AFs). To identify possible genetic targets to reduce AF contamination, in this study, we have characterized a novel Set3, and it shares sequence homology with the yeast protein Set3. The deletion mutants present no difference in growth rate but alterations in asexual development and secondary metabolite production when compared to the wild type. Specifically, deletion of gene decreases conidiophore formation and conidial production through downregulating expression of and genes. In addition, normal levels of are required for sclerotial development and expression of sclerotia-related genes and . Further analyses demonstrated that Set3 negatively regulates AF production as well as the concomitant expression of genes in the AF gene cluster. Importantly, our results also display that Set3 is involved in crop kernel colonization. Taking together, these results reveal that a novel Set3 plays crucial roles in morphological development, secondary metabolism, and fungal virulence in .
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http://dx.doi.org/10.3389/fmicb.2019.00530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455067PMC
March 2019

The HosA Histone Deacetylase Regulates Aflatoxin Biosynthesis Through Direct Regulation of Aflatoxin Cluster Genes.

Mol Plant Microbe Interact 2019 Sep 31;32(9):1210-1228. Epub 2019 Jul 31.

Fujian Key Laboratory of Pathogenic Fungi Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

Histone deacetylases (HDACs) always function as corepressors and sometimes as coactivators in the regulation of fungal development and secondary metabolite production. However, the mechanism through which HDACs play positive roles in secondary metabolite production is still unknown. Here, classical HDAC enzymes were identified and analyzed in , a fungus that produces one of the most carcinogenic secondary metabolites, aflatoxin B (AFB1). Characterization of the HDACs revealed that a class I family HDAC, HosA, played crucial roles in growth, reproduction, the oxidative stress response, AFB1 biosynthesis, and pathogenicity. To a lesser extent, a class II family HDAC, HdaA, was also involved in sclerotia formation and AFB1 biosynthesis. An in vitro analysis of HosA revealed that its HDAC activity was considerably diminished at nanomolar concentrations of trichostatin A. Notably, chromatin immunoprecipitation experiments indicated that HosA bound directly to AFB1 biosynthesis cluster genes to regulate their expression. Finally, we found that a transcriptional regulator, SinA, interacts with HosA to regulate fungal development and AFB1 biosynthesis. Overall, our results reveal a novel mechanism by which classical HDACs mediate the induction of secondary metabolite genes in fungi.
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http://dx.doi.org/10.1094/MPMI-01-19-0033-RDOI Listing
September 2019

TCTP promotes epithelial-mesenchymal transition in lung adenocarcinoma.

Onco Targets Ther 2019 27;12:1641-1653. Epub 2019 Feb 27.

Department of Respiratory Medicine, The Second Affiliated Hospital of Air Force Medical University, Xi'an, People's Republic of China,

Background: Lung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial-mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP's expression is associated with EMT in lung adenocarcinoma is largely unknown.

Methods: Several Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan-Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.

Results: TCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.

Conclusion: TCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429.
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http://dx.doi.org/10.2147/OTT.S184555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398409PMC
February 2019

Use of Interferon-γ release assay for the diagnosis of female genital tuberculosis in Northwest China.

J Clin Lab Anal 2019 Jan 13;33(1):e22621. Epub 2018 Jul 13.

Department of Respiration, Tangdu hospital, the Second Affiliated Hospital of Air Force Medical University, Xi'an, China.

Background: Female genital tuberculosis (FGTB) is one of the major causes of infertility. However, nonspecific manifestations and the lack of easy access to gold-standard diagnostic test render a diagnostic difficult for FGTB. The objective of this study was to determine T-SPOT.TB (an interferon-γ release assay, IGRA) performance in patients with FGTB.

Methods: A total of 213 female patients with validated T-SPOT.TB results were recruited in this retrospective study. Among which, 103 were confirmed FGTB, and 110 were excluded from tuberculosis (control). Of the confirmed FGTB patients, 52 were confirmed by microbiologically/histopathologically examination, while the remaining 51 were clinically confirmed (successfully responsive to anti-tuberculosis treatment). T-SPOT.TB test was performed in both FGTB and control group during the diagnostic procedure.

Results: The overall sensitivity and specificity of T-SPOT.TB were 86.41% and 75.45% respectively. Sensitivity of T-SPOT.TB was significantly higher when compared with conventional tuberculosis diagnostic tests. Moreover, T-SPOT.TB test using pelvic effusion (PE) showed higher sensitivity than using corresponding peripheral blood (PB) (94.44% vs 72.22%, P < 0.001). Mean value of spot forming cells (SFCs) of T-SPOT.TB using PE was significantly higher than that of PB in FGTB group (193 (IQR 105-280) SFCs/2.5 × 10 PEMCs vs 71 (IQR 36-107) SFCs/2.5 × 10 PBMCs, P = 0.01), while this was not detected in control group (11 (IQR 0-22) SFCs/2.5 × 10 PEMCs vs 9 (IQR 0-18) SFCs/2.5 × 10 PBMCs, P = 0.77).

Conclusion: These results demonstrated that T-SPOT.TB, especially PE T-SPOT.TB, is an useful adjunct in FGTB diagnosis.
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http://dx.doi.org/10.1002/jcla.22621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430357PMC
January 2019

Tracing the dynamic expression of the Nfκb2 gene during inflammatory processes by in vivo bioluminescence imaging in transgenic mice.

Biochem Biophys Res Commun 2018 06 27;501(1):41-47. Epub 2018 Apr 27.

School of Life Science & Technology, Tongji University, Shanghai, 200092, China; Shanghai Engineering Research Center for Model Organisms, SRCMO/SMOC, Shanghai, 201203, China. Electronic address:

Nfκb2(p52/p100) plays essential roles in many chronic inflammatory diseases. Tracing the dynamic expression of Nfκb2 during different biological processes in vivo can provide valuable clues to understand the biological functions of this gene and develop anti-inflammatory drugs. In this study, B6-Tg(Nfκb2-luc) transgenic mouse line, a mouse model in which the expression of firefly luciferase gene is under the control of a 14.6-kb mouse Nfκb2 promoter, was generated to monitor the expression of p52/p100 in vivo. Bioluminescence imaging was used for tracking the luciferase signal in living mice in a variety of inflammatory processes, including LPS-induced sepsis and inflammatory bowel disease (IBD). The data of in vivo bioluminescence imaging in this mouse model showed that luciferase activity coincided with the endogenous p52/p100 expression. Moreover, dexamethasone or aspirin, two routine anti-inflammatory drugs, could decrease the high-level expression of luciferase induced by LPS. Overall, our results suggest that the B6-Tg(Nfκb2-luc) mice represent a valuable reporter mouse model not only to monitor the expression of p52/p100 in physiological or pathological processes but also to evaluate the effects of various anti-inflammatory drug treatments in vivo.
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http://dx.doi.org/10.1016/j.bbrc.2018.04.126DOI Listing
June 2018

Investigation of Aspergillus flavus in animal virulence.

Toxicon 2018 Apr 2;145:40-47. Epub 2018 Mar 2.

Fujian Key Laboratory of Pathogenic Fungi Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China. Electronic address:

Aspergillus flavus is a common fungal pathogen of plants, animals and humans. Recently, many genes of A. flavus have been reported involving in regulation of pathogenesis in crops, but whether these genes are involved in animal virulence is still unknown. Here, we used a previous easy-to-use infection model for A. flavus based on mouse model by intravenous inoculation of A. flavus conidia. The outcome of infections in mice model showed that A. flavus NRRL3357 and laboratory strain CA14 PTS were both in dose dependent manner and highly reproducible. The progress of disease could be monitored by mice survival and histology analysis. Fungal burden analysis indicated it was gradually decreased within 7 days after infection. Moreover, aspergillosis caused by A. flavus significantly up-regulated gene expression levels of immune response mediators, including INF-γ, TNF-α, Dectin-1 and TLR2. Furthermore, the defined deletion A. flavus strains that previously displayed virulence in crop infection were also determined in this mouse model, and the results showed comparable degrees of infection in mice. Our results suggested that intravenous inoculation of conidia could be a suitable model for testing different A. flavus mutants in animal virulence. We hope to use this model to determine distinct A. flavus strains virulence in animals and study novel therapeutic methods to help control fungus diseases in the future.
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http://dx.doi.org/10.1016/j.toxicon.2018.02.043DOI Listing
April 2018

Generation of knock-in cynomolgus monkey via CRISPR/Cas9 editing.

Cell Res 2018 Mar 12;28(3):379-382. Epub 2018 Jan 12.

Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

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http://dx.doi.org/10.1038/cr.2018.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835779PMC
March 2018

Fate tracing of hepatocytes in mouse liver.

Sci Rep 2017 11 23;7(1):16108. Epub 2017 Nov 23.

School of Life Science and Techonology, Tongji University, Shanghai, 200092, China.

Hepatocytes perform most of the functions of the liver and are considered terminally differentiated cells. Recently, it has been suggested that hepatocytes might have the potential to transdifferentiate or dedifferentiate under physiological or pathological conditions in vivo. Epithelial-mesenchymal transition of hepatocytes in liver fibrosis has also been proposed. However, these findings have not been fully confirmed. In this study, hepatocytes were genetically labelled for cell fate tracing using lacZ via the tamoxifen-induced CreERT/loxP system. After induction with tamoxifen, alb + cells were permanently marked by lacZ expression, and all progeny lacZ + cells were derived from a single source with no interference. We did not observe transdifferentiation or dedifferentiation of hepatocytes into cholangiocytes or hepatic progenitor cells under conditions of liver homeostasis or following a 2/3 partial hepatectomy. Meanwhile, lacZ/OPN-positive cells were observed in livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed mice, and lacZ/alpha-smooth muscle actin-positive cells were detected in carbon tetrachloride-induced chronic liver injury models. These results suggested that some existing differentiated alb + cells might have the potential of transdifferentiation/dedifferentiation or epithelial-to-mesenchymal transition in vivo in some liver injury models, but the proportion of these alb + cells in liver was very low, and their significance and actual function during the pathological process remains to be elucidated.
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http://dx.doi.org/10.1038/s41598-017-15973-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701080PMC
November 2017

Enhancing the precision of genetic lineage tracing using dual recombinases.

Nat Med 2017 Dec 13;23(12):1488-1498. Epub 2017 Nov 13.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), University of Chinese Academy of Sciences, Shanghai, China.

The Cre-loxP recombination system is the most widely used technology for in vivo tracing of stem or progenitor cell lineages. The precision of this genetic system largely depends on the specificity of Cre recombinase expression in targeted stem or progenitor cells. However, Cre expression in nontargeted cell types can complicate the interpretation of lineage-tracing studies and has caused controversy in many previous studies. Here we describe a new genetic lineage tracing system that incorporates the Dre-rox recombination system to enhance the precision of conventional Cre-loxP-mediated lineage tracing. The Dre-rox system permits rigorous control of Cre-loxP recombination in lineage tracing, effectively circumventing potential uncertainty of the cell-type specificity of Cre expression. Using this new system we investigated two topics of recent debates-the contribution of c-Kit cardiac stem cells to cardiomyocytes in the heart and the contribution of Sox9 hepatic progenitor cells to hepatocytes in the liver. By overcoming the technical hurdle of nonspecific Cre-loxP-mediated recombination, this new technology provides more precise analysis of cell lineage and fate decisions and facilitates the in vivo study of stem and progenitor cell plasticity in disease and regeneration.
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http://dx.doi.org/10.1038/nm.4437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913096PMC
December 2017

Endothelial semaphorin 7A promotes seawater aspiration-induced acute lung injury through plexin C1 and β1 integrin.

Mol Med Rep 2017 Oct 27;16(4):4215-4221. Epub 2017 Jul 27.

Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.

Inflammation and edema are two main characteristics in seawater aspiration‑induced acute lung injury (ALI). In a previous study of the authors, it was demonstrated that endothelial semaphorin 7A (SEMA7A) serves an important role in the development of seawater‑induced inflammation and edema. However, the mechanism of endothelial SEMA7A‑mediated ALI remains unclear. Therefore, the authors explored the effect of SEMA7A in rat pulmonary microvascular endothelial cells (RPMVECs) and the interaction between endothelial SEMA7A and alveolar macrophages during seawater aspiration‑induced ALI. The role of SEMA7A in endothelial permeability was detected using plexin C1 blocking antibody or SEMA7A small interfering (si)RNA. In addition, RPMVECs were co‑cultured with rat alveolar macrophage cell line‑NR8383 cells and pro‑inflammatory cytokine production was detected. Interaction between the β1 integrin and SEMA7A was detected using the β1 integrin blocking antibody or SEMA7A siRNA. Seawater stimulation induced endothelial cytoskeleton remodeling, endothelial permeability, phosphorylation of cofilin, and increased the vascular endothelial growth factor (VEGF) expression in RPMVECs. Moreover, seawater stimulation led to expression of proinflammatory cytokines and activated the nuclear factor‑κB pathway in co‑cultured cells. However, blockage with the plexin C1 antibody inhibited endothelial cytoskeleton remodeling, endothelial permeability, phosphorylation of cofilin, and treatment with SEMA7A siRNA inhibited expression of VEGF in RPMVECs. In addition, blockage with β1 integrin antibody reduced expression of proinflammatory cytokines and inhibited activation of NF‑κB in co‑culture cells. These results suggest that SEMA7A promotes seawater induced lung edema via plexin C1 and stimulates seawater induced lung inflammation via β1 integrin.
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http://dx.doi.org/10.3892/mmr.2017.7097DOI Listing
October 2017

CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice.

Hum Genet 2017 07 15;136(7):875-883. Epub 2017 May 15.

Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Room C613, Building for School of Life Sciences, Fudan University, No. 2005 Songhu Rd, Shanghai, 200433, China.

Hemophilia B (HB) is an X-linked disorder caused by defects of F9 encoded coagulation factor IX, which is an ideal model for gene therapy. Most existing HB gene therapies are based on viral mediated gene supplementation, which could increase immunoreaction. In this study, CRISPR/Cas9 system was used for gene correction in an F9 mutant HB mouse model in both adult mice (in vivo) and in germline cells (ex vivo). In vivo, naked Cas9-sgRNA plasmid and donor DNA were delivered to HB mice livers to recover the mutation via hydrodynamic tail vein (HTV) injection. 62.5% of the HTV-treated mice showed a detectable gene correction (>1%) in the F9 alleles of hepatocytes, which was sufficient to remit the coagulation deficiency. Ex vivo, three different forms of Cas9 were microinjected into germline cells of HB mice to investigate their efficiency and safety in gene correction. Cas9 protein showed higher gene recovery rates, less embryo toxicity, and lower mosaic repair percentage, making it more suitable for germline gene therapy. Our study strongly supports that CRISPR/Cas9-mediated genome editing is feasible in gene therapy of genetic disorders.
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http://dx.doi.org/10.1007/s00439-017-1801-zDOI Listing
July 2017

The Aspergillus flavus Histone Acetyltransferase AflGcnE Regulates Morphogenesis, Aflatoxin Biosynthesis, and Pathogenicity.

Front Microbiol 2016 30;7:1324. Epub 2016 Aug 30.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, The Ministry of Education Key Laboratory of Biopesticide and Chemical Biology, and School of Life Sciences, Fujian Agriculture and Forestry University Fuzhou, China.

Histone acetyltransferases (HATs) help regulate fungal development and the production of secondary metabolites. In this study, we determined that the HAT AflGcnE influenced morphogenesis and aflatoxin biosynthesis in Aspergillus flavus. We observed that AflGcnE localized to the nucleus and cytoplasm during the conidial production and germination stages, while it was located mainly in the nucleus during the hyphal development stage. Deletion of AflgcnE inhibited the growth of A. flavus and decreased the hydrophobicity of the cell surface. The ΔAflgcnE mutant exhibited a lack of asexual sporulation and was unable to generate sclerotia. Additionally, AflgcnE was required to maintain cell wall integrity and genotoxic stress responses. Importantly, the ΔAflgcnE mutant did not produce aflatoxins, which was consistent with a significant down-regulation of aflatoxin gene expression levels. Furthermore, our data revealed that AflgcnE is a pathogenicity factor required for colonizing maize seeds. In summary, we revealed that A. flavus AflGcnE is crucial for morphological development, aflatoxin biosynthesis, stress responses, and pathogenicity. Our findings help clarify the functional divergence of GcnE orthologs, and may provide a possible target for controlling A. flavus infections of agriculturally important crops.
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http://dx.doi.org/10.3389/fmicb.2016.01324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003836PMC
September 2016

N-myc is a key switch regulating the proliferation cycle of postnatal cerebellar granule cell progenitors.

Sci Rep 2015 Aug 4;5:12740. Epub 2015 Aug 4.

School of Life Science and Technology, Tongji University. Shanghai 200092, China.

N-myc plays an important role in early cerebellar development; however, the role of N-myc in postnatal cerebellar development is still unknown. In this study, inducible and reversible N-myc mouse models (Nmyc(TRE/TRE):tTS and Nmyc(EGFP/TRE):tTS) are used to regulate and track the expression of endogenous N-myc in vivo. Loss of N-myc at the neonatal stage results in reduced proliferation of granule cell precursors (GCPs) and reduced cerebellar volume/mass. Restoration of N-myc expression no later than postnatal day 4 can rescue the cerebellar developmental defect caused by the absence of N-myc after birth. During cerebellar postnatal development, N-myc acts as a key switch, regulating the proliferation cycle of postnatal granule cell progenitors. Loss of N-myc significantly impairs the Sonic hedgehog signalling pathway, and disrupts the expression of cell cycle effectors with a significant reduction of Ccnd2. More importantly, N-myc negatively regulates the expression of microRNA-9 during postnatal cerebellar development. Our findings demonstrate that over-expression of miR-9 can inhibit the proliferation of GCPs. The regulation of these factors by N-myc is at least partly responsible for the switch role of N-myc in the proliferation cycle of GCPs.
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http://dx.doi.org/10.1038/srep12740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523855PMC
August 2015