Shanghai Research Center for Model Organisms

Shanghai, China

Shanghai Research Center for Model Organisms

Shanghai, China
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Lu T.,East China Normal University | Dang S.,Shanghai JiaoTong University | Dang S.,Shanghai Research Center for Model Organisms | Zhu R.,East China Normal University | And 4 more authors.
Oncotarget | Year: 2017

ADAMTS18 is a novel tumor suppressor and is critical to the pathology of human colorectal cancer. However, the underlying mechanism is not clear. Here we generated an Adamts18-deficient mouse strain as an in vivo model to investigate the role of ADAMTS18 in the pathogenesis of colorectal cancer. In AOM/DSS-induced colitisassociated colorectal cancer, the deficiency of Adamts18 in mice resulted in enhanced tumorigenesis and colon inflammation that could be attributed in part to enhanced nuclear translocation of β-catenin and elevated expression of its downstream target genes, cyclin D1 and c-myc. Moreover, increased p38MAPK and ERK1/2 activities were detected in colon cancer cells from Adamts18-deficient mice. Further studies revealed that ADAMTS18 deficiency reduced intestinal E-cadherin levels in mice, which ultimately led to intestinal barrier dysfunction. These data indicate that Adamts18 deficiency enhances tumorigenesis and intestinal inflammation through elevated Wnt/β-catenin and p38MAPK/ERK1/2 signaling and promotes colon cancer in this mouse model.

Xu W.-Y.,Shanghai JiaoTong University | Gu M.-M.,Shanghai JiaoTong University | Sun L.-H.,Shanghai JiaoTong University | Guo W.-T.,Shanghai JiaoTong University | And 14 more authors.
American Journal of Human Genetics | Year: 2012

Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies. Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2. Genome-wide linkage analysis showed that the disease phenotype is closely linked to chromosomal region 10p13-14, which spans 5.41 Mb between D10S585 and D10S1477. DNA-sequencing analysis revealed a nonsense mutation, c.1455T>G (p.Tyr485lowast), in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals, but not in other unaffected individuals in this family or in 250 unrelated normal persons. DHTKD1 mRNA expression levels in peripheral blood of affected persons were observed to be half of those in unaffected individuals. In vitro studies have shown that, compared to wild-type mRNA and DHTKD1, mutant mRNA and truncated DHTKD1 are significantly decreased by rapid mRNA decay in transfected cells. Inhibition of nonsense-mediated mRNA decay by UPF1 silencing effectively rescued the decreased levels of mutant mRNA and protein. More importantly, DHTKD1 silencing was found to lead to impaired energy production, evidenced by decreased ATP, total NAD+ and NADH, and NADH levels. In conclusion, our data demonstrate that the heterozygous nonsense mutation in DHTKD1 is one of CMT2-causative genetic alterations, implicating an important role for DHTKD1 in mitochondrial energy production and neurological development. © 2012 The American Society of Human Genetics.

Yang C.-G.,Shanghai JiaoTong University | Wang W.-G.,Shanghai Research Center for Model Organisms | Yan J.,Shanghai JiaoTong University | Fei J.,Shanghai Research Center for Model Organisms | And 2 more authors.
Molecular Medicine Reports | Year: 2013

The aim of this study was to investigate the effects and possible mechanisms of ghrelin receptor (GHS-R) deficiency on gastric motility in GHS-R deficient (Ghsr-/-) mice. Ghsr-/- and control (Ghsr +/+) mice were genotyped by PCR. The percentage of gastric emptying (GE%) was calculated following the intraperitoneal administration of ghrelin. In vitro, the contractile response of smooth muscle strips to ghrelin and electrical field stimulation (EFS) and the intraluminal pressure change of isolated stomach to carbachol were observed in an organ bath. The staining of nerve cells in the gastric muscle layer was performed by immunofluorescence. Delayed gastric emptying was observed in the Ghsr-/- mice; ghrelin enhanced the GE% in the Ghsr+/+ mice but had no effect on the GE% in the Ghsr-/- mice. In vitro, the response of the strips to ghrelin and EFS and the intraluminal pressure change to cabarchol was reduced in the Ghsr-/- mice. GHS-Rs were predominantly expressed on nerve cells in gastric muscle layers. The number of nerve cells was observed to be decreased in the Ghsr-/- mice. The delayed gastric emptying may relate to the loss of GHS-Rs and the reduction in the number of nerve cells in the gastric muscle layers of the GHS-R-deficient mice. © 2013 Spandidos Publications Ltd.

Hu X.-L.,CAS Shanghai Institutes for Biological Sciences | Cheng X.,CAS Shanghai Institutes for Biological Sciences | Fei J.,Tongji University | Fei J.,Shanghai Research Center for Model Organisms | Xiong Z.-Q.,CAS Shanghai Institutes for Biological Sciences
Epilepsia | Year: 2011

Purpose: The ketogenic diet (KD) has been used as an effective antiepileptic treatment for nearly a century. Inhibition of glycolysis and increased levels of ketone bodies are both known to contribute to the antiepileptic effects of the KD. Neuron-restrictive silencer factor (NRSF), also known as RE-1 silencing transcription factor (REST), is implicated in the antiepileptic effects of the glycolytic inhibitor 2-deoxy-d-glucose (2DG). Glycolytic inhibition is a common feature of the KD and 2DG treatment, leading to the hypothesis that NRSF might also be involved in the antiepileptic effect of the KD. To test this hypothesis, the present study was designed to investigate the role of NRSF in the antiepileptic effect of 2DG, the KD, and acetone in vivo. Methods: Kindling was used as a model to test the antiepileptic effects of 2DG, the KD, and acetone on control and NRSF conditional knockout mice (NRSF-cKO; from the intercross of CamKIIα-iCre and NRSF exon 2 floxed mice). After recovery from electrode implantation, adult mice were stimulated twice a day at afterdischarge threshold (ADT) current intensity. In the 2DG- (500 mg/kg) and acetone- (10 mmol/kg) treated groups, drugs were injected intraperitoneally 20 min before each stimulus. In the 2DG group, mice were pretreated with intraperitoneal injections for 3 days in addition to the injections administered before the regular kindling stimulation. In the KD group, mice were fed the KD instead of a control diet until the end of stimulations. Key Findings: Compared with control mice, the antiepileptic effect of 2DG was abolished in NRSF-cKO mice, indicating that NRSF is required for the antiepileptic effect of 2DG. In the KD-fed group, kindling development was retarded in both control and NRSF-cKO mice. In the acetone-treated group, inhibition of kindling-induced epileptogenesis was observed in both control and NRSF-cKO mice, similar to the action of the KD. Significance: These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet. © 2011 International League Against Epilepsy.

Yang P.,Tongji University | Cai G.,Shanghai Research Center for Model Organisms | Cai Y.,Shanghai Research Center for Model Organisms | Fei J.,Tongji University | Liu G.,U.S. National Institute on Aging
Acta Biochimica et Biophysica Sinica | Year: 2013

Attention deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impaired sustained attention, impulsivity, and is usually accompanied by varying degrees of learning difficulties and lack of motor coordination. However, the pathophysiology and etiology of ADHD remain inconclusive so far. Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-) is hyperactive and exhibited impaired memory performance in the Morris water maze. In the current study, we found that the gat1-/- mice showed low levels of attentional focusing and increased impulsivity. In addition, the gat1-/- mice displayed ataxia characterized by defects in motor coordination and balance skills. The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine. Collectively, these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD. © The Author 2013. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

Sun R.,Shanghai Research Center for Model Organisms | Zhao K.,Tongji University | Shen R.,Shanghai Research Center for Model Organisms | Cai L.,Shanghai Research Center for Model Organisms | And 7 more authors.
Nucleic Acids Research | Year: 2012

Methods for generating loss-of-function mutations, such as conventional or conditional gene knockout, are widely used in deciphering gene function in vivo. By contrast, inducible and reversible regulation of endogenous gene expression has not been well established. Using a mouse model, we demonstrate that a chimeric transcriptional repressor molecule (tTS) can reversibly inhibit the expression of an endogenous gene, Nmyc. In this system, a tetracycline response element (TRE) artificially inserted near the target gene's promoter region turns the gene on and off in a tetracycline-inducible manner. NmycTRE mice were generated by inserting a TRE into the first intron of Nmyc by the knockin technique. NmycTRE mice were crossed to tTS transgenic mice to produce NmycTRE/TRE: tTS embryos. In these embryos, tTS blocked Nmyc expression, and embryonic lethality was observed at E11.5d. When the dam was exposed to drinking water containing doxycycline (dox), normal endogenous Nmyc expression was rescued, and the embryo survived to birth. This novel genetic modification strategy based on the tTS-dox system for inducible and reversible regulation of endogenous mouse genes will be a powerful tool to investigate target genes that cause embryonic lethality or other defects where reversible regulation or temporary shutdown of the target gene is needed. © 2012 The Author(s).

Yu M.,Fudan University | Suo H.,Fudan University | Liu M.,Tongji University | Cai L.,Shanghai Research Center for Model Organisms | And 8 more authors.
Neurobiology of Aging | Year: 2013

Parkinson's disease (PD) is characterized by progressing loss of dopaminergic neurons in the midbrain. Abnormal gene expression plays a critical role in its pathogenesis. Neuron-restrictive silencer factor (NRSF)/neuronal repressor element-1 silencing transcription factor (REST), a member of the zinc finger transcription factors, inhibits the expression of neuron-specific genes in nonneuronal cells, and regulates neurogenesis. Our previous work showed that 1-methyl-4-phenyl-pyridinium ion triggers dynamic changes of messenger RNA and protein expression of NRSF in human dopaminergic SH-SY5Y cells, and alteration of NRSF expression exacerbates 1-methyl-4-phenyl-pyridinium ion-induced cell death. The purpose of this study was to explore the in vivo role of NRSF in the progress of PD by using NRSF/REST neuron-specific conditional knockout mice (cKO). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in the cKO mice and wild type littermates. At 1, 3, 7, 14, 21, and 28 days after MPTP injection, behavioral tests were performed, and cKO mice displayed some impairments in locomotor activities. Also, the reduction of tyrosine hydroxylase protein in the striatum and the loss of dopaminergic neurons in the substantia nigra were more severe in the cKO mice. Meanwhile, the cKO mice exhibited a more dramatic depletion of striatal dopamine, accompanied by an increase in glial fibrillary acidic protein (GFAP) expression and sustained interleukin-1β transcription. These results suggested that NRSF/REST neuronal cKO mice are more vulnerable to the dopaminergic neurotoxin MPTP. Disturbance of the homeostasis of NRSF and its target genes, gliogenesis, and inflammation may contribute to the higher MPTP sensitivity in NRSF/REST neuronal cKO mice. © 2013 Elsevier Inc.

Ying Y.,Tongji University | Yang X.,Tongji University | Zhao K.,Tongji University | Mao J.,Shanghai Research Center for Model Organisms | And 5 more authors.
Nucleic Acids Research | Year: 2015

The Krüppel-associated box (KRAB) domain is a transcription repression module from the largest family of transcriptional regulators encoded by higher vertebrates. We developed a drug-controllable regulation system based on an artificial KRAB-containing repressor (tTS) that targets the endogenous Hprt gene to explore the regulatory mechanism and molecular basis of KRAB-containing regulators within the context of an endogenous gene in vivo. We show that KRAB can mediate irreversible and reversible regulation of endogenous genes in mouse that is dependent on embryonic developmental stage. KRAB-induced stable DNA methylation within the KRAB binding region during the early embryonic stage, resulting in irreversible gene repression. In later stages, KRAB mainly induced deacetylation and methylation of histone, resulting in reversible gene repression. Thus, we have characterized the KRAB-mediated regulation system within the context of an endogenous gene and multiple spatiotemporal ranges, thereby providing a basis for identifying the function of KRAB-containing regulators and aiding development of novel KRAB-based gene regulation tools in vivo. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Ma M.,Tongji University | Zhao K.,Tongji University | Wu W.,Shanghai Research Center for Model Organisms | Sun R.,Shanghai Research Center for Model Organisms | And 2 more authors.
Development Growth and Differentiation | Year: 2014

N-myc belongs to the Myc oncogene family and plays an essential role in mammalian embryonic development. The expression of N-myc is dynamically regulated during embryonic development; however, its expression pattern has not been well characterized due to the lack of a suitable animal model. In this paper, a genetically modified mouse model was generated in which the enhanced green fluorescent protein (EGFP) coding sequence was inserted into the N-myc locus, so that endogenous N-myc expression could be traced by the signal of EGFP. The EGFP signal in the transgenic mouse was confirmed to be consistent with the expression pattern of endogenous N-myc by fluorescence microscopy and immunohistochemical staining. Furthermore, the spatial and temporal expression of EGFP was observed in the central and peripheral nervous system, heart, lung and kidney, given the known indispensable role of N-myc in their formation. EGFP was also strongly detected in the liver, paranephros and the epithelium of the intestine. The EGFP signal can be used to trace N-myc expression in this transgenic mouse model. N-myc expression was observed in specific locations and cell lineages, and dynamically changed during embryonic development. The changing N-myc expression pattern seen in mouse embryonic development and the animal model described in this paper provide important insights and a new tool to research N-myc function. © 2014 Japanese Society of Developmental Biologists.

Shanghai Research Center For Model Organisms and Shanghai Biomodel Organism Science & Technology Development Co. | Date: 2012-09-10

The invention discloses a kit which comprises a formulation containing artemisinin or the derivatives thereof, a formulation containing ribonuclease, and a specification.

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