A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit

Endocrinology. 2000 Jul;141(7):2557-66. doi: 10.1210/endo.141.7.7550.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn / genetics*
  • Animals, Newborn / growth & development
  • Anti-Bacterial Agents
  • Base Sequence / genetics
  • DNA Transposable Elements
  • Directed Molecular Evolution
  • Drug Resistance, Microbial / genetics
  • Female
  • Gene Targeting*
  • Growth Disorders / genetics*
  • Humans
  • Introns / genetics
  • Male
  • Mice
  • Molecular Sequence Data
  • Neomycin
  • Phenotype
  • RNA Splicing / genetics*
  • Receptor, IGF Type 1 / genetics*
  • Somatomedins / metabolism


  • Anti-Bacterial Agents
  • DNA Transposable Elements
  • Somatomedins
  • Receptor, IGF Type 1
  • Neomycin