title: Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice.
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.
authors.affiliation: Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, 26006, Logroño, Spain.
authors.forename: Icíar Paula
authors.initials: IP
authors.lastname: López
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rodriguez-de la Rosa
authors.forename: Rosete Sofia
authors.initials: RS
authors.lastname: Pais
authors.forename: Sergio
authors.initials: S
authors.lastname: Piñeiro-Hermida
authors.forename: Raquel
authors.initials: R
authors.lastname: Torrens
authors.forename: Julio
authors.initials: J
authors.lastname: Contreras
authors.forename: Isabel
authors.initials: I
authors.lastname: Varela-Nieto
authors.forename: José García
authors.initials: JG
authors.lastname: Pichel
mesh_terms: D000818:Animals; D001835:Body Weight; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics*; D013154:Spleen / Q000187:drug effects / Q000254:growth & development; D013629:Tamoxifen / Q000008:administration & dosage; D013737:Testis / Q000254:growth & development
chemical_list: D012333:RNA, Messenger; D013629:Tamoxifen; D017526:Receptor, IGF Type 1; C045073:Cre recombinase; D019426:Integrases