Abstract
SUMMARYUnderstanding 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
Insulin-like growth factor-1 (IGF1) plays a pivotal role in fetal development, growth and tissue homeostasis
The knock-in D (KID) and knock-in R3-IGF1 (KIR) mutant proteins have reduced affinity for the IGF-binding proteins (IGFBPs), and present as unbound insulin-like growth factor-1 (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
Insulin-like growth factor-1 (IGF1) plays a pivotal role in fetal development, growth and tissue homeostasis. Igf1-null mice have marked growth retardation in utero and weigh 65% of normal weight at birth (Baker et al, 1993; Liu et al, 1998). Igf1null mice do not undergo a peri-pubertal growth spurt and weigh only 30% of adult wild-type 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. Despite the this observation must be taken cautiously because GH aforementioned phenotype, KID and KIR female mice can support levels were measured only once per mouse
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