[Physiology of somatotropic axis: interest of gene inactivation experiments]

Research into the somatotropic axis (growth hormone, insulin-like growth factors) has received renewed attention in the last few years, owing to techniques for genetic modification in the mouse, essentially transgenesis, and gene inactivation. The results, compared with phenotypic and molecular data for various pathological conditions, e.g. short stature, have increased our understanding of the function of the various parameters of the somatotropic axis, especially those of the insulin-like growth factor (IGF) system. During fetal development, IGF-II (which is subject to imprinting) and IGF-I are essential for increases in height and weight and for development of the various organs, adipose tissue in particular. The action of these two IGF is mediated by the IGF type 1 receptor. Total inactivation of the IGF-I gene, the paternal allele of the IGF-II gene or the IGF type 1 receptor gene leads to growth retardation resulting in mouse fetuses weighing only 60%, 60% and 45% of their wild-type controls. Combinations of these inactivations have shown that IGF-II also exerts its effects by interacting with another, as yet uncharacterized receptor. Moreover, inactivation of the IGF-I gene specifically in the liver, organ which normally maintains the high IGF-I concentrations in the blood (endocrine action), has no effect on growth, demonstrating that local IGF-I plays an auto/paracrine role in the periphery, under the direct influence of growth hormone (GH). However, endocrine IGF-I plays an important role in metabolism and cellular proliferation, and its function in mitosis may favor the development of cancer in the breast, colon and prostate. Mice with homozygous inactivation of the IGF type 1 receptor gene are not viable after birth. Partial and conditional inactivation have made it possible to study the physiology of these factors in adult animals. In contrast to IGF-II, the IGF type 1 receptor is, like IGF-I, involved in postnatal growth regulation. Lack of IGF type 1 receptor or of IGF-I affects both height and weight, and shows that this receptor is particularly involved in promoting pubertal growth. The activated receptor acts differently and specifically in each tissue. Finally, the IGF type 1 receptor has recently been implicated in the control of lifespan: a 50% decrease in the number of receptors increased the lifespan of these mice by 26%. This increase displayed sexual dimorphism, being greater for females (33%) than for males (16%). Invalidations combining different properties--specificities according to tissue, development stage or inducibility by an exogenous product--will facilitate fine dissection of the roles of the various ubiquitous actors in the IGF system.