Efficient generation of selection‐gene‐free rat knockout models by homologous recombination in ES cells

He, Lixia; Li, Shuping; Guo, Zihang; Men, Hongsheng; Wu, Yuanyuan; Li, Ning; Bryda, Elizabeth C.; Capecchi, Mario R.; Wu, Sen

doi:10.1002/1873-3468.12388

Cited by 7 publications

(5 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Csf1r knockout rats described here join a small set of rat knockout lines that have been produced via homologous recombination in ESC ((48) and reviewed in (13)). The comparison between rat and mouse mutant phenotypes supports the view that the rat, in many cases, provides a superior model for studying human genetic disease.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

Pridans

Raper

Davis

et al. 2018

The Journal of Immunology

109

128

View full text Add to dashboard Cite

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r−/− rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

Pridans

Raper

Davis

et al. 2018

The Journal of Immunology

109

128

View full text Add to dashboard Cite

show abstract

“…The nutrition content per kg premix formula feed is listed in Table 1 . The Leptin −/− r ats were generated by the Sen Wu laboratory [ 11 ]. Both wild type and Leptin −/− rats were provided with the same always abundant manufactured diet (Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis

Tan,

Song,

et al. 2023

Cell Biosci

View full text Add to dashboard Cite

Background Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic hepatic disease and results in non-alcoholic steatohepatitis (NASH), which progresses to fibrosis and cirrhosis. Although the Leptin deficient rodent models are widely used in study of metabolic syndrome and obesity, they fail to develop liver injuries as in patients. Methods Due to the high similarity with humans, we generated Leptin-deficient (Leptin−/−) pigs to investigate the mechanisms and clinical trials of obesity and NAFLD caused by Leptin. Results The Leptin−/− pigs showed increased body fat and significant insulin resistance at the age of 12 months. Moreover, Leptin−/− pig developed fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis with age. Absence of Leptin in pig reduced the phosphorylation of JAK2-STAT3 and AMPK. The inactivation of JAK2-STAT3 and AMPK enhanced fatty acid β-oxidation and leaded to mitochondrial autophagy respectively, and both contributed to increased oxidative stress in liver cells. In contrast with Leptin−/− pig, although Leptin deletion in rat liver inhibited JAK2-STAT3 phosphorylation, the activation of AMPK pathway might prevent liver injury. Therefore, β-oxidation, mitochondrial autophagy and hepatic fibrosis did not occurred in Leptin−/− rat livers. Conclusions The Leptin-deficient pigs presents an ideal model to illustrate the full spectrum of human NAFLD. The activity of AMPK signaling pathway suggests a potential target to develop new strategy for the diagnosis and treatment of NAFLD.

show abstract

“…As shown in Supplemental Table 5, the nutrition content of pig diets were changed with age. The Leptin -/rats were generated by the Sen Wu laboratory (11). Both wild type and Leptin -/rats were provided with the same always abundant manufactured diet (Table S5).…”

Section: Experimental Animalsmentioning

confidence: 99%

Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

Tan

Song

Wang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN deficient LEPTIN --//--) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity . The LEPTIN pigs showed increased body fat and significant insulin resistance by 12 months of age . To resemble non alcoholic fatty liver disease (NAFLD) patients , LEPTIN pig developed the phenotypic features of fatty liver, non alcoholic steatohepatitis ( and hepatic fibrosis with age. Mean while, LEPTIN absence reduced phosphorylation of JAK2 STAT3 and AMPK. The alteration of JAK2 STAT3 enhanced fatty acid β oxidation, whereas inactivation of AMPK le d to mitochondrial autophagy, and both contributed to increased oxidative 2stress in hepatocytes . Although Leptin deletion in the rat liver altered JAK2 STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis i n contrast with the LEPTIN pig. To our knowledge, the LEPTIN pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis . The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.

show abstract

Efficient generation of selection‐gene‐free rat knockout models by homologous recombination in ES cells

Cited by 7 publications

References 36 publications

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis

Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

Contact Info

Product

Resources

About