Genetics of Growth: Roles o fInsulin-like Growth Factors (IGFs) in Development and Tumorigenesis

Growth, considered as an increase in size until a limit is attained, is a fundamental developmental process. In mammals, the body size limit, which is correlated with a variety of physiological parameters, is determined by the rate and duration of cell proliferation. During embryogenesis, growth, and also differentiation, are thought to occur by differential expression of hierarchies of genes functioning in a cascade fashion through complex developmental pathways. Genes encoding polypeptide growth factors and their receptors are among the key regulatory elements that provide combinations of products playing pivotal roles in the control of proliferative and determinative events in these developmental cascades.

The mammalian IGF family consists of two ligands (IGF-I and IGF-II), two receptors (type 1 and type 2; IGF1R and IGF2R) and at least six binding proteins (IGF-BPs). The main focus of the laboratory is the analysis of the developmental functions of the IGF system by a genetic approach using predominantly mutant mice generated by targeting of the Igf1, Igf2, Igf1r, Igf2r and Igf-bp3 genes. In addition, the gene encoding the growth hormone receptor was disrupted, to analyze the relationship between the roles of growth hormone and IGF-I in postnatal growth.

The manifestation of either severe growth deficiency or overgrowth as a consequence of the particular targeted mutations studied revealed unequivocally that the IGF system is a major, if not the most important growth determinant during development. This paradigm re-emphasizes the view that in mammalian organisms the growth process is mostly genetically controlled. Comparison of the phenotypes of the IGF null mutations, alone or in combination (double and triple mutants), in terms of embryonic growth kinetics, birthweights, developmental delays or histopathology in particular tissues, and survival after birth defined the onset of mutational events and the in vivo relationships in ligand/receptor interactions. The results showed that IGF1R serves in vivo the signaling of both IGF-I and IGF-II, while the growth-promoting function of IGF-II is mediated in part through an additional interaction with the insulin receptor. IGF2R, on the other hand, serves for degradation of excess IGF-II. Interestingly, in the case of the IGF gene system, growth regulation is also influenced by the epigenetic process of parental imprinting (i.e. monoallelic gene expression depending on parental legacy).

In parallel, based on evidence about the involvement of IGF1R functions in tumor development, the laboratory has initiated an exploration of the role of the IGFs in cancer, with emphasis on mammary tumorigenesis. Thus, we are testing whether the severity of mammary tumors in transgenic mice that inevitably develop them could be reduced in genetic backgrounds lacking functions of the IGF system. In this context, to provide models of hereditary breast cancer, we are pursuing conditional mutagenesis of the Brca1 and Brca2 genes.

Selected Publications:

DeChiara T.M., Robertson E.J. and Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64: 849-859 (1991).

Liu J-P, Baker J., Perkins A.S., Robertson E.J. and Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type-1 IGF receptor (Igf1r). Cell 75: 59-72 (1993).

Baker J., Liu J-P, Robertson E.J. and Efstratiadis. A Role of IGFs in embryonic and postnatal growth. Cell 75: 73-82 (1993).

Efstratiadis A. Parental imprinting of autosomal mammalian genes. Curr Opin Genet Devel 4: 265-280, (1994).

Baker J., Hardy M.P., Zhou J., Bondy C., Lupu F., Bellvé A.R. and Efstratiadis A. Effects of an Igf1 gene null mutation on mouse reproduction. Mol Endocrinol 10: 903-918 (1996).

Ludwig T., Eggenschwiler J., Fisher P., D'Ercole A.J., Davenport M.L. and Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev Biol 177: 517-535 (1996).

Ludwig T., Chapman D.L., Papaioannou V.E. and Efstratiadis A. Targeted mutations of breast cancer susceptibility genes in mice: Lethal phenotypes of Brca1, Brca2, Brca1/Brca2 , Brca1/p53 , and Brca2/p53 nullizygous embryos. Genes & De.l 11:1226-1241 (1997).

Louvi, A., Accili, D. and Efstratiadis, A. (1997). Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev. Biol., 189, 33-48.

Eggenschwiler, J., Ludwig, T., Fisher, P., Leighton, P., Tilghman, S.M. and Efstratiadis, A. Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes. Genes & Dev. 11, 3128-3142 (1997).

Louvi, A., Accili, D. and Efstratiadis, A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev. Biol., 189, 33-48 (1997).

Politi, K., Szabolcs, M., Fisher, P., Kljuic, A., Ludwig, T., and Efstratiadis, A. A mouse model of uterine leiomyosarcoma. American Journal of Pathology.  in press (Supplementary Data)