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.
Highlights
During the development of transgenic technologies in mice it was realized that homologous and heterologous intronic sequences and polyadenylation signals are essential for the stabilization and efficient expression of the transgene of interest[1, 2]
We show that the expression of the human growth hormone (hGH) minigene in the CollagenVI expressing mesenchymal cells in various tissues can lead to previously undescribed alterations in mouse physiology
Our findings describe for the first time the plethora of local and/or systemic effects that the hGH minigene can have when expressed in the mesenchymal compartment
Summary
During the development of transgenic technologies in mice it was realized that homologous and heterologous intronic sequences and polyadenylation signals are essential for the stabilization and efficient expression of the transgene of interest[1, 2]. In order to study the role of TNF-TNFR1 signaling in the mesenchyme in a humanized background, we generated the TgC6hp[55] transgenic mice which, to the mouse Tnfr[1], express the human TNFR1 in the mesenchymal compartment under the control of the Col6a1 ( CollagenVI or ColVI) promoter[25] It has been previously shown in transgenic embryos that the CollagenVI promoter is active in mesenchymal cells in many different tissues like skin insertions of the superficial aponeurosis, joints, nerves, intervertebral discs, vibrissae, skeletal muscle, meninges, tendons, subepidermal mesenchyme, heart, blood vessels, adipose tissue, cartilage, central nervous system and retina (ectopic expression), while there are some hints for expression in other tissues like lungs, intestine, kidney, periosteum, perichondrium, serosae, bladder[25]. Our findings describe for the first time the plethora of local and/or systemic effects that the hGH minigene can have when expressed in the mesenchymal compartment
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