Postnatally elevated levels of insulin-like growth factor (IGF)-II fail to rescue the dwarfism of IGF-I-deficient mice except kidney weight.
This study tested whether elevated levels of IGF-II in the postnatal period can rescue the dwarfism in IGF-I-deficient mice. Heterozygous Igf1 mutant mice [I(+/-) II(wt)] were crossed with heterozygous Igf1 mutant, phosphoenolpyruvate carboxykinase promoter IGF-II transgenic mice [I(+/-) II(tg)], and [I(+/+) II(wt)], [I(+/+) II(tg)], [I(-/-) II(wt)], and [I(-/-) II(tg)] offspring were investigated. IGF-II levels were 11- and 6-fold higher in male and female [I(-/-) II(tg)] vs. [I(-/-) II(wt)] animals. Western ligand blot analysis revealed markedly reduced activities of 30- and 32-kDa IGF binding proteins (IGFBPs) (most likely IGFBP-1 and IGFBP-2) and the 39- to 43-kDa IGFBP-3 double band in serum from IGF-I-deficient mice. These binding proteins were partially restored by overexpression of IGF-II. Analysis of weight data from the early postnatal period until d 60 showed that, in the absence of IGF-I, elevated levels of IGF-II have no effect on body weight gain. A detailed analysis of body proportions, bone parameters, and organ weights of 60-d-old mice also failed to show effects of IGF-II with one important exception: in Igf1 mutant and also Igf1 intact male mice, IGF-II overexpression significantly increased absolute (+32.4 and +28.6%; P < 0.01) and relative kidney weights (+29.0 and +22.4%; P < 0.001). These changes in kidney weight were associated with reduced phosphorylation of p38 MAPK. In summary, our genetic model shows that substantial amounts of IGF-II in the circulation do not rescue the postnatal growth deficit of IGF-I-deficient mice but increase absolute and relative kidney weights of normal and IGF-I-deficient male mice, suggesting a gender-specific role of IGF-II for kidney growth.
Moerth
Corinna
C
Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, D-81377 Munich, Germany.
Schneider
Marlon R
MR
Renner-Mueller
Ingrid
I
Blutke
Andreas
A
Elmlinger
Martin W
MW
Erben
Reinhold G
RG
Camacho-Hübner
Cecilia
C
Hoeflich
Andreas
A
Wolf
Eckhard
E
D000818:Animals; D021461:Animals, Outbred Strains; D049628:Body Size; D001835:Body Weight; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006579:Heterozygote; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D048051:p38 Mitogen-Activated Protein Kinases