Abstract
SUMMARY Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.
Highlights
Insulinlike growth factor1 (IGF1) plays a pivotal role in fetal development, growth and tissue homeostasis
The knockin D (KID) and knockin R3IGF1 (KIR) mutant proteins have reduced affinity for the IGFbinding proteins (IGFBPs), and present as unbound insulinlike growth factor1 (IGF1), or ‘free IGF1’. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels
Ternary complex formation of IGF1 with the IGFBPs and the acid labile subunit (ALS) was markedly reduced in sera from KID and KIR mice compared with wild type
Summary
Insulinlike growth factor1 (IGF1) plays a pivotal role in fetal development, growth and tissue homeostasis. Igf1null mice do not undergo a peripubertal growth spurt and weigh only 30% of adult wildtype animals. These mice are infertile, indicating that IGF1 plays an essential role in the reproductive system. At 8 weeks of age, both KID and KIR female mice showed an increase in the mean serum GH levels, probably owing to reduced serum IGF1 levels and an impaired inhibitoryfeedback mechanism. This observation must be taken cautiously because GH levels were measured only once per mouse.
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