Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development.

Genetic analyses of dwarfing phenotypes resulting from targeted mutagenesis of the genes encoding the insulin-like growth factors (IGF-I and IGF-II) and their cognate type 1 IGF receptor (IGF1R) have demonstrated that this signaling system is a major determinant of mouse embryonic growth. Of the two IGF ligands, IGF-I interacts exclusively with IGF1R, whereas IGF-II recognizes an additional receptor (XR), because the growth retardation of embryos lacking both IGR1R and IGF-II (30% of normal birthweight) is more severe than that manifested in either class of single Igf1r or Igf2 null mutants (45 and 60% of normal, respectively). To determine whether XR is the insulin receptor (IR), we examined embryos nullizygous for both Igf1r and Insr. While the growth of embryos lacking solely IR is affected very mildly and only at the end of gestation, concomitant absence of IGF1R results in a severe growth-deficiency phenotype (30% of normal size at birth) that is first detected at Embryonic Day 13.5 and is also characterized by transient edema, curly tail, generalized organ hypoplasia, including the muscles, developmental delays in ossification, and thin epidermis. The Igf1r/Insr double nullizygotes are phenotypically indistinguishable from double mutants lacking IGF1R and IGF-II and from other double and triple mutants in which all of the IGF ligand/receptor interactions have been eliminated. Therefore, these results provide genetic evidence that the growth-promoting function of IGF-II during mouse embryogenesis is mediated in part by signaling through the insulin receptor.

[1]  R. Joshi,et al.  Phenotypic alterations in insulin-deficient mutant mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Gruss,et al.  The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas , 1997, Nature.

[3]  R. Furlanetto,et al.  Homozygous nonsense mutation in the insulin receptor gene of a patient with severe congenital insulin resistance: leprechaunism and the role of the insulin‐like growth factor receptor , 1996, Clinical endocrinology.

[4]  B. Weintraub Molecular endocrinology : basic concepts and clinical correlations , 1995 .

[5]  D. Accili Molecular defects of the insulin receptor gene. , 1995, Diabetes/metabolism reviews.

[6]  B. Hoflack,et al.  Roles for mannose-6-phosphate receptors in lysosomal enzyme sorting, IGF-II binding and clathrin-coat assembly. , 1995, Trends in cell biology.

[7]  Y. Patel,et al.  A Study of the Structural and Biochemical Development of Human Fetal Islets of Langerhans , 1982, Diabetes.

[8]  D. Accili,et al.  Mutations in the insulin receptor gene. , 1992, Endocrine reviews.

[9]  I. Lisse,et al.  Agenesis of pancreas , 1994, Acta paediatrica.

[10]  K. Nicolaides,et al.  Plasma insulin in appropriate- and small-for-gestational-age fetuses. , 1989, American journal of obstetrics and gynecology.

[11]  A. Mclaren,et al.  GENETIC AND ENVIRONMENTAL EFFECTS ON FOETAL AND PLACENTAL GROWTH IN MICE. , 1965, Journal of reproduction and fertility.

[12]  D. Accili,et al.  Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism , 1995, Human mutation.

[13]  E. Wagner,et al.  Regulation of embryonic growth and lysosomal targeting by the imprintedIgf2/Mpr gene , 1994, Nature.

[14]  K. Becker,et al.  Pancreatic Insulin Content of Nonpregnant, Pregnant and Postpartum Rats and the Developing Rat Fetus , 1969, Diabetes.

[15]  T. Ludwig,et al.  Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. , 1996, Developmental biology.

[16]  R. Bailey The comparative growth of Efe pygmies and African farmers from birth to age 5 years. , 1991, Annals of human biology.

[17]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[18]  J. Félix,et al.  Circulating Insulin and Tissular Reactivity to Insulin in the Rat During the Perinatal Period , 1971, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[19]  J. Girard,et al.  Glucose-induced increase of plasma insulin in the rat foetus in utero. , 1974, The Journal of endocrinology.

[20]  K. Teramo,et al.  Human Fetal Insulin Metabolism Early in Gestation: Response to Acute Elevation of the Fetal Glucose Concentration and Placental Transfer of Human Insulin-I-131 , 1969, Diabetes.

[21]  F. Biddle Genetically determined transient edema found in the WB/ReJ mouse strain in a teratogenic survey with acetazolamide. , 1990, Teratology.

[22]  M. Savage,et al.  Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. , 1996, The New England journal of medicine.

[23]  B. Hogan,et al.  PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. , 1996, Development.

[24]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[25]  C T Roberts,et al.  Molecular and cellular aspects of the insulin-like growth factor I receptor. , 1995, Endocrine reviews.

[26]  W. Clarke,et al.  Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. , 1993, American journal of diseases of children.

[27]  M. Wilder,et al.  Secretion and Content of Insulin and Glucagon in Human Fetal Pancreas Slices in Vitro 1 , 1973, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[28]  E. M. Otis,et al.  Equivalent ages in mouse and human embryos , 1954, The Anatomical record.

[29]  A. Copp,et al.  The embryonic development of mammalian neural tube defects , 1990, Progress in Neurobiology.

[30]  A. Efstratiadis,et al.  Parental imprinting of autosomal mammalian genes. , 1994, Current opinion in genetics & development.

[31]  Adolph Ef Physiological stages in the development of mammals. , 1970 .

[32]  Tyler Sa,et al.  Dynamics of normal growth. , 1965 .

[33]  A. Efstratiadis,et al.  Parental imprinting of the mouse insulin-like growth factor II gene , 1991, Cell.

[34]  Simeon I. Taylor,et al.  Homozygous deletion of the human insulin receptor gene results in leprechaunism , 1993, Nature Genetics.

[35]  K. Shima,et al.  Insulin content and enzyme histochemistry of the human foetal pancreatic islet. , 1966, The Journal of endocrinology.

[36]  T. Shepard,et al.  The ontogenesis of human fetal hormones. I. Growth hormone and insulin. , 1972, The Journal of clinical investigation.

[37]  W. Rutter,et al.  Early differentiation of glucagon-producing cells in embryonic pancreas: a possible developmental role for glucagon. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Edlund,et al.  Insulin-promoter-factor 1 is required for pancreas development in mice , 1994, Nature.

[39]  K. Laurence,et al.  Congenital absence of islets of Langerhans. , 1977, Archives of disease in childhood.

[40]  E. Schon,et al.  RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon , 1985, Molecular and cellular biology.

[41]  N. Bersch,et al.  Insulin-like growth factor I resistance in immortalized T cell lines from African Efe Pygmies. , 1995, The Journal of clinical endocrinology and metabolism.

[42]  J. Baker,et al.  Effects of an Igf1 gene null mutation on mouse reproduction. , 1996, Molecular endocrinology.

[43]  B. Lamothe,et al.  Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. , 1996, The EMBO journal.

[44]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[45]  K. Méhes,et al.  Agenesis of pancreas and gall-bladder in an infant of incest. , 1976, Acta paediatrica Academiae Scientiarum Hungaricae.

[46]  D. Barlow,et al.  The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus , 1991, Nature.

[47]  D. Accili,et al.  Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients , 1990, Diabetes Care.

[48]  H. Werner,et al.  Developmental regulation of the rat insulin-like growth factor I receptor gene. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Gluckman,et al.  Clinical review 68: The endocrine regulation of fetal growth in late gestation: the role of insulin-like growth factors. , 1995, The Journal of clinical endocrinology and metabolism.

[50]  A. Leiter,et al.  Expression of peptide YY in all four islet cell types in the developing mouse pancreas suggests a common peptide YY-producing progenitor. , 1994, Development.

[51]  H. Edlund,et al.  IPF1, a homeodomain protein with a dual function in pancreas development. , 1995, The International journal of developmental biology.

[52]  J. Vonesch,et al.  Genetic analysis of RXRα developmental function: Convergence of RXR and RAR signaling pathways in heart and eye morphogenesis , 1994, Cell.

[53]  J. Thorell Plasma insulin levels in normal human foetuses. , 1970, Acta endocrinologica.

[54]  McEvoy Rc,et al.  Pancreatic insulin-, glucagon-, and somatostatin-positive islet cell populations during the perinatal development of the rat. II. Changes in hormone content and concentration. , 1980 .

[55]  S. Driscoll,et al.  The Extractable Insulin Content of Pancreas from Fetuses and Infants of Diabetic and Control Mothers , 1965, Diabetes.

[56]  M. Lyon,et al.  Mouse chromosome atlas. , 1990 .

[57]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[58]  Philip L. Altman,et al.  Biology Data Book , 1975 .

[59]  H. Hathaway,et al.  The developmental pathology of maternally derived Thp fetuses. , 1988, Teratology.

[60]  Ziying Liu,et al.  Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. , 1994, Genes & development.

[61]  B. Hogan,et al.  Manipulating the mouse embryo: A laboratory manual , 1986 .

[62]  R. Baserga,et al.  Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[63]  B. Ursø,et al.  The Insulin-Like Growth Factor-I Receptor , 1994, Hormone Research.

[64]  D. Leroith Insulin-like Growth Factors: Molecular and Cellular Aspects , 1991 .

[65]  J. Barber,et al.  Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. , 1996, Human molecular genetics.

[66]  R. Evans,et al.  RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. , 1994, Genes & development.

[67]  M. C. Green,et al.  Catalog of mutant genes and polymorphic loci. , 1981 .

[68]  Simeon I. Taylor,et al.  Leprechaunism and homozygous nonsense mutation In the insulin receptor gene , 1993, The Lancet.

[69]  M. Jonas,et al.  Congenital diabetes mellitus and fatal secretory diarrhea in two infants. , 1991, Journal of pediatric gastroenterology and nutrition.

[70]  J. Vera,et al.  Decreased insulin-like growth factor I receptor expression and function in immortalized African Pygmy T cells. , 1996, The Journal of clinical endocrinology and metabolism.

[71]  William L. Clarke,et al.  Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence , 1997, Nature Genetics.

[72]  Margaret C. Green,et al.  Genetic variants and strains of the laboratory mouse , 1981 .

[73]  Matthew H. Kaufman,et al.  The Atlas of Mouse Development , 1992 .

[74]  L. Orci,et al.  Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. , 1991, Development.

[75]  R. Rugh,et al.  The mouse; its reproduction and development , 1968 .

[76]  L. Orci,et al.  A Quantitative Immunofluorescent Study of the Endocrine Cell Populations in the Developing Human Pancreas , 1983, Diabetes.

[77]  S. O’Rahilly,et al.  Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism , 1993, The Lancet.

[78]  A. Efstratiadis,et al.  A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting , 1990, Nature.

[79]  J. Girard,et al.  Factors Affecting the Secretion of Insulin and Glucagon by the Rat Fetus , 1974, Diabetes.

[80]  S. Kornfeld Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. , 1992, Annual review of biochemistry.

[81]  K. Hall,et al.  Insulin-like growth factors and their binding proteins. , 1990, Physiological reviews.

[82]  Mark D. Johnson,et al.  Early neonatal death in mice homozygous for a null allele of the insulin receptor gene , 1996, Nature Genetics.

[83]  R. Roth,et al.  Cellular distribution of insulin-degrading enzyme gene expression. Comparison with insulin and insulin-like growth factor receptors. , 1994, The Journal of clinical investigation.

[84]  H. Hahn,et al.  Age-dependent Insulin Secretion of the Endocrine Pancreas In Vitro from Fetuses of Diabetic and Nondiabetic Patients , 1983, Diabetes Care.

[85]  T. Takeuchi,et al.  Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. , 1995, Genes & development.

[86]  B. Burguera,et al.  The Insulin-Like Growth Factor-II/Mannose 6-Phosphate Receptor , 1989 .