A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit.
The insulin-like growth factor (IGF) system is a major regulator of somatic growth in vertebrates. Both ligands (IGF-I and IGF-II) signal via the same IGF receptor (IGF-IR). Classical IGF-IR invalidation is lethal at birth, so that conditional models are needed to study the postnatal role of this receptor. To establish a genetically inducible invalidation of IGF-IR, we targeted the IGF-IR gene using a construct that introduced a neomycin resistance cassette into intron 2, leaving the rest of the gene intact. This neomycin resistance cassette interfered with the processing of the primary transcript, resulting in there being 12% fewer IGF-binding sites at the cell surface in heterozygous mice and 41% fewer in homozygous mice. Hetero- and homozygous offspring grew more slowly than their wild-type littermates. This difference was noticeable from 4 weeks after birth and was significant from 5 weeks after birth in males. In females, the effect on postnatal growth of insertion of the neo cassette was not significant. In males, IGF-I levels increased moderately (+26%) but significantly, indicating effective feedback regulation of the IGF system. IGF-binding protein-4 (IGFBP-4) levels, estimated by Western ligand blotting, were low in homozygotes (-38%), whereas IGFBP-1, -2, and -3 levels were unaffected. In females, IGF-I and IGFBP-1, -2, -3, and -4 levels did not differ significantly among heterozygous, homozygous, and wild-type animals. We investigated the molecular mechanism involved and characterized two RNA-splicing events that could account for the decrease in IGF-IR. The phenotype of these mice developed exclusively postnatally, and body proportions were maintained. IGF-IRneo mice constitute a new model for human postnatal growth deficiency.
Holzenberger
M
M
U-515 INSERM, Hôpital Saint-Antoine, Paris, France. holzenberger@st-antoine.inserm.fr
Leneuve
P
P
Hamard
G
G
Ducos
B
B
Perin
L
L
Binoux
M
M
Le Bouc
Y
Y
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics* / Q000254:growth & development; D000900:Anti-Bacterial Agents; D001483:Base Sequence / Q000235:genetics; D004251:DNA Transposable Elements; D019020:Directed Molecular Evolution; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009355:Neomycin; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D013002:Somatomedins / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements; D013002:Somatomedins; D017526:Receptor, IGF Type 1; D009355:Neomycin