NOVEL INSIGHTS INTO THE INSULIN-LIKE GROWTH FACTOR 1 SYSTEM REVEALED BY STUDIES OF NEW MUTANT MOUSE MODELS

NOVEL INSIGHTS INTO THE INSULIN-LIKE GROWTH FACTOR 1 SYSTEM REVEALED BY STUDIES OF NEW MUTANT MOUSE MODELS

By Victoria E. DeMambro

Thesis Advisor: Dr. Clifford J. Rosen

A Lay Abstract of the Thesis Presented

in Partial Fulfillment of the Requirements for the

Degree of Master of Science

(in Biochemistry)

May, 2010

            The insulin-like growth factor system (IGF) is a major growth regulatory network in mice and humans. Investigations of two mouse models with genetic mutations in insulin-like growth factor binding protein 2 (IGFBP-2) and insulin receptor substrate 1 (IRS-1), two proteins that are part of this network, are reported here. Studies of the first model in which IGFBP-2 has been genetically removed (Igfbp2 null or Igfbp2^-/- mice) revealed that male Igfbp2^-/- mice were heavier,had shorter femurs, smaller spleens and increased circulating IGF-I levels compared to controls. Female Igfbp2^-/- mice had increased bone mass, while male Igfbp2^-/- mice had reduced bone mass compared to controls. A marker of bone formation, osteocalcin was reduced in male and increased in female Igfbp2^-/- mice. Igfbp2^-/- male mice were found to have reductions in bone cell number and bone formation rates. Phosphatase and tensin homolog (PTEN), a protein shown to have deleterious effects on IGF activity and bone formation, levels were increased in the Igfbp2^-/- mice pointing to a potential cause of the bone defects exhibited. The second model investigated, a spontaneous mouse mutant, designated 'small' (sml), was found to contain a mutation in the Irs1 gene resulting in loss of protein function. The mutant (Irs1^sml/sml) mice are small, lean, hearing impaired, have 20% less circulating IGF-I, are hyperinsulinemic and are mildly insulin resistant compared to control littermates. Irs1^sml/sml mice have low bone mass and formation rates. Irs1^sml/smlbone cells treated with IGF-I exhibited increased IRS-2 activity suggesting compensation between the two protein family members. Thus, these studies suggest a new role for IGFBP-2 in bone development modified by gender, having implications for the gender-biased progression of osteoporosis in humans. Furthermore, the demonstration of an unanticipated heterozygous phenotype in the Irs1^+/sml mice suggests that similar mutations in IRS-1 in humans may be responsible for short stature and/or osteoporosis. In summary, systematic investigation of the Igfbp2^-/- and Irs1^sml/smlmice demonstrate the power of mouse mutant gene models to reveal novel insights into the biological actions of the IGF-I system.