Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression
Abstract The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minig...
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oai:doaj.org-article:911ee4b399e34f6197bd564c883bb7052021-12-02T12:32:15ZExtensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression10.1038/s41598-017-02581-82045-2322https://doaj.org/article/911ee4b399e34f6197bd564c883bb7052017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02581-8https://doaj.org/toc/2045-2322Abstract The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minigene in TgC6hp55 transgenic mice which express the human TNFR1 under the control of the mesenchymal cell-specific CollagenVI promoter. These mice displayed a fully penetrant phenotype characterized by growth enhancement accompanied by perturbations in metabolic, skeletal, histological and other physiological parameters. Notably, this phenotype was independent of TNF-TNFR1 signaling since the genetic ablation of either Tnf or Tradd did not rescue the phenotype. Further analyses showed that the hGH minigene was expressed in several tissues, also leading to increased hGH protein levels in the serum. Pharmacological blockade of GH signaling prevented the development of the phenotype. Our results indicate that the unplanned expression of the hGH minigene in CollagenVI expressing mesenchymal cells can lead through local and/or systemic mechanisms to enhanced somatic growth followed by a plethora of primary and/or secondary effects such as hyperphagia, hypermetabolism, disturbed glucose homeostasis, altered hematological parameters, increased bone formation and lipid accumulation in metabolically critical tissues.Aimilios KaklamanosJan RozmanManolis RoulisNiki KaragianniMaria ArmakaMoya WuLaura BrachthäuserJulia Calzada-WackMarion HorschJohannes BeckersBirgit RathkolbThure AdlerFrauke NeffEckhard WolfValerie Gailus-DurnerHelmut FuchsMartin Hrabe de AngelisGeorge KolliasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) |
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Medicine R Science Q Aimilios Kaklamanos Jan Rozman Manolis Roulis Niki Karagianni Maria Armaka Moya Wu Laura Brachthäuser Julia Calzada-Wack Marion Horsch Johannes Beckers Birgit Rathkolb Thure Adler Frauke Neff Eckhard Wolf Valerie Gailus-Durner Helmut Fuchs Martin Hrabe de Angelis George Kollias Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| description |
Abstract The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minigene in TgC6hp55 transgenic mice which express the human TNFR1 under the control of the mesenchymal cell-specific CollagenVI promoter. These mice displayed a fully penetrant phenotype characterized by growth enhancement accompanied by perturbations in metabolic, skeletal, histological and other physiological parameters. Notably, this phenotype was independent of TNF-TNFR1 signaling since the genetic ablation of either Tnf or Tradd did not rescue the phenotype. Further analyses showed that the hGH minigene was expressed in several tissues, also leading to increased hGH protein levels in the serum. Pharmacological blockade of GH signaling prevented the development of the phenotype. Our results indicate that the unplanned expression of the hGH minigene in CollagenVI expressing mesenchymal cells can lead through local and/or systemic mechanisms to enhanced somatic growth followed by a plethora of primary and/or secondary effects such as hyperphagia, hypermetabolism, disturbed glucose homeostasis, altered hematological parameters, increased bone formation and lipid accumulation in metabolically critical tissues. |
| format |
article |
| author |
Aimilios Kaklamanos Jan Rozman Manolis Roulis Niki Karagianni Maria Armaka Moya Wu Laura Brachthäuser Julia Calzada-Wack Marion Horsch Johannes Beckers Birgit Rathkolb Thure Adler Frauke Neff Eckhard Wolf Valerie Gailus-Durner Helmut Fuchs Martin Hrabe de Angelis George Kollias |
| author_facet |
Aimilios Kaklamanos Jan Rozman Manolis Roulis Niki Karagianni Maria Armaka Moya Wu Laura Brachthäuser Julia Calzada-Wack Marion Horsch Johannes Beckers Birgit Rathkolb Thure Adler Frauke Neff Eckhard Wolf Valerie Gailus-Durner Helmut Fuchs Martin Hrabe de Angelis George Kollias |
| author_sort |
Aimilios Kaklamanos |
| title |
Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| title_short |
Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| title_full |
Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| title_fullStr |
Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| title_full_unstemmed |
Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression |
| title_sort |
extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hgh minigene expression |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/911ee4b399e34f6197bd564c883bb705 |
| work_keys_str_mv |
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