Abstract
Insulin-like growth factor type 1 receptor (IGF1R) is a ubiquitously expressed tyrosine kinase that regulates cell proliferation, differentiation and survival. It controls body growth and organ homeostasis, but with specific functions depending on developmental time and cell type. Human deficiency in IGF1R is involved in growth failure, microcephaly, mental retardation and deafness, and its overactivation is implicated in oncogenesis. Igf1r-deficient mice die at birth due to growth retardation and respiratory failure. Although multiple Igf1r tissue-specific mutant lines have been analyzed postnatally, using Igf1r-floxed (Igf1r fl/fl) mice mated with diverse cell-type recombinase Cre-expressing transgenics, no mouse models for the study of generalized Igf1r deficiency in adults have been reported. To this end we generated UBC-CreERT2; Igf1r fl/fl transgenic mice with an inducible deletion of Igf1r activated by tamoxifen. Tamoxifen administration to 4 week-old prepuberal male mice delayed their growth, producing a distinct impact on organ size 4 weeks later. Whereas testes were smaller, spleen and heart showed an increased organ to body weight ratio. Mosaic Igf1r genomic deletions caused a significant reduction in Igf1r mRNA in all organs analyzed, resulting in diverse phenotypes. While kidneys, spleen and cochlea had unaltered gross morphology, testes revealed halted spermatogenesis, and liver and alveolar lung parenchyma showed increased cell proliferation rates without affecting apoptosis. We demonstrate that UBC-CreERT2 transgenic mice efficiently delete Igf1r upon postnatal tamoxifen treatment in multiple mouse organs, and corroborate that IGF1R function is highly dependent on cell, tissue and organ type.
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Acknowledgments
We thank our summer student, A. Santos, for her effort in cell quantitation, L. Ochoa (Centro de Investigación Biomédica de La Rioja-CIBIR, Spain) for help with liver histology interpretation and D. Santamaría (CNIO, Spain) for giving advice about the UBC-CreERT2 transgenic line. We are grateful to Drs. J. Brüning (University of Cologne, Germany) and E. Brown (UPENN School of Medicine, PA) for providing Igf1r fl/fl and UBC-CreERT2 mutant mouse lines, respectively. The authors would also like to thank Maria Cruz Gabaldón for excellent technical assistance. This work was partially supported by Grants from the Fundación Rioja Salud (Logroño, Spain) to JGP, and from Ministerio de Ciencia e Innovación (SAF2011-24391), the 7th Framework Programme projects AFHELO and TARGEAR to IVN. RSP was a pre-doctoral fellow from Fundación Rioja Salud and LRdR holds a CIBERER contract.
Ethical standard
All experiments and animal procedures were carried out in accordance with the current EU legislation on the protection of animals used for scientific purposes (2010/63/UE), in compliance with National Legislation of Spain, and revised and approved by the CIBIR Bioethics Committee (Logroño).
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López, I.P., Rodriguez-de la Rosa, L., Pais, R.S. et al. Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice. Transgenic Res 24, 279–294 (2015). https://doi.org/10.1007/s11248-014-9837-5
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DOI: https://doi.org/10.1007/s11248-014-9837-5