The Soluble Type 2 Insulin-like Growth Factor (IGF-II) Receptor Reduces Organ Size by IGF-II-mediated and IGF-II-independent Mechanisms

Abstract

The soluble type 2 insulin-like growth factor (IGF) receptor or IGF-II/mannose 6-phosphate receptor (sIGF2R) is produced in vivo by proteolytic deletion of the transmembrane and intracellular domains of the cellular form of the receptor (IGF2R). There is evidence that sIGF2R is a negative regulator of growth. We have shown that transgenic mice expressing anIgf2r cDNA with a deleted transmembrane domain sequence (sΔIgf2r) show reduced local organ size. In the present study, we investigate whether sΔIGF2R can slow the growth induced by an excess of IGF-II and whether the biological activity of sΔIGF2R is due solely to its interactions with IGF-II. To this end, we crossed sΔIgf2r transgenics by mice overexpressing IGF-II (Blast line) or by mice carrying a disrupted paternal (active) allele of the Igf2 gene (Igf2 m+/p−). Analysis of the phenotypes revealed that the soluble IGF2R affects the size of some organs (colon and cecum) exclusively by reducing the biological activity of IGF-II, whereas in other organs (stomach and skin) the biological activity of the receptor is at least in part independent of IGF-II and must involve an interaction with other factor(s). The soluble type 2 insulin-like growth factor (IGF) receptor or IGF-II/mannose 6-phosphate receptor (sIGF2R) is produced in vivo by proteolytic deletion of the transmembrane and intracellular domains of the cellular form of the receptor (IGF2R). There is evidence that sIGF2R is a negative regulator of growth. We have shown that transgenic mice expressing anIgf2r cDNA with a deleted transmembrane domain sequence (sΔIgf2r) show reduced local organ size. In the present study, we investigate whether sΔIGF2R can slow the growth induced by an excess of IGF-II and whether the biological activity of sΔIGF2R is due solely to its interactions with IGF-II. To this end, we crossed sΔIgf2r transgenics by mice overexpressing IGF-II (Blast line) or by mice carrying a disrupted paternal (active) allele of the Igf2 gene (Igf2 m+/p−). Analysis of the phenotypes revealed that the soluble IGF2R affects the size of some organs (colon and cecum) exclusively by reducing the biological activity of IGF-II, whereas in other organs (stomach and skin) the biological activity of the receptor is at least in part independent of IGF-II and must involve an interaction with other factor(s). insulin-like growth factor-II peptide type 2 insulin-like growth factor receptor or IGF-II/mannose 6-phosphate receptor polypeptide soluble IGF2R polypeptide transmembrane domain-deleted transgenic sIGF2R transforming growth factor-β1 polymerase chain reaction base pair(s). The growth and survival factor insulin-like growth factor II (IGF-II)1 binds to at least three different receptors: the type 1 and 2 IGF receptors and IGF2R (also known as the mannose 6-phosphate/IGF-II receptor) and the insulin receptor. Type 1 IGF receptor and the insulin receptor are members of the tyrosine kinase receptors family and mediate most of the biological effects of IGF-II (1Stewart C.E.H. Rotwein P. Physiol. Rev. 1996; 76: 1005-1026Crossref PubMed Scopus (698) Google Scholar, 2Louvi A. Accili D. Efstradiatis A. Dev. Biol. 1997; 189: 33-48Crossref PubMed Scopus (327) Google Scholar). Genetic evidence suggests that the IGF2R gene encodes a negative regulator of growth. Many human tumors show loss of heterozygosity at the IGF2R locus frequently accompanied by mutations in the remaining allele (3Hankins G.R. De Souza A.T. Bentley R.C. Patel M.R. Marks J.R. Iglehart J.D. Jirtle R.L. Oncogene. 1996; 12: 2003-2009PubMed Google Scholar, 4Ouyang H. Shiwaku H.O. Hagiwara H. Miura K. Abe T. Kato Y. Ohtani H. Shiiba K. Souza R.F. Meltzer S.J. Horii A. Cancer Res. 1997; 57: 1851-1854PubMed Google Scholar, 5Yamada T. De Souza A.T. Finkelstein S. Jirtle R.L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10351-10355Crossref PubMed Scopus (190) Google Scholar). Furthermore, mice in which the Igf2r gene is disrupted are born 25–35% bigger than controls (6Wang Z-Q. Fung M, R. Barlow D.P. Wagner E.F. Nature. 1994; 372: 464-467Crossref PubMed Scopus (408) Google Scholar, 7Lau M.M.H. Stewart C.E.H. Liu Z. Bhatt H. Rotwein P. Stewart C.L. Genes Dev. 1994; 8: 2953-2963Crossref PubMed Scopus (475) Google Scholar, 8Ludwig T. Eggenschwiler J. Fisher P. D'Ercole A.J. Davenport M.L. Efstradiatis A. Dev. Biol. 1996; 177: 517-535Crossref PubMed Scopus (406) Google Scholar). IGF2R is a multifunctional protein that participates in the activation of TGF-β1, regulates lysosomal enzymes trafficking, and binds a number of ligands including proliferin, herpes simplex virus glycoprotein D, thyroglobulin, and retinoic acid (9Kornfeld S. Annu. Rev. Biochem. 1992; 61: 307-330Crossref PubMed Scopus (936) Google Scholar, 10Oka Y. Rozek L.M. Czech M.P. J. Biol. Chem. 1985; 260: 9435-9442Abstract Full Text PDF PubMed Google Scholar, 11Hille-Rehfeld A. Biochim. Biophys. Acta. 1995; 1241: 177-194Crossref PubMed Scopus (218) Google Scholar, 12Dahms N.M. Biochem. Soc. Trans. 1996; 24: 136-141Crossref PubMed Scopus (38) Google Scholar, 13Dennis P.A. Rifkin D.B. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 580-584Crossref PubMed Scopus (460) Google Scholar, 14Kang J.X. Li Y. Leaf A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13671-13676Crossref PubMed Scopus (117) Google Scholar). A soluble form of IGF2R (sIGF2R) is produced by proteolytic cleavage of the transmembrane and intracellular domains of the membrane form of the receptor and is present in the serum, amniotic fluid, and urine of rodents and humans. sIGF2R binds IGF-II with high affinity in vivo and can bind mannose 6-phosphate in vitro, suggesting that it shares at least some of its ligand specificity with the membrane IGF2R (15Kiess W. Greenstein L.A. White R.M. Lee L. Rechler M.M. Nissley S.P. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7720-7724Crossref PubMed Scopus (88) Google Scholar, 16Causin C. Waheed A. Braulke T. Junghans U. Maly P. Humbel R.E. von Figura K. Biochem. J. 1988; 252: 795-799Crossref PubMed Scopus (75) Google Scholar, 17MacDonald R.G. Tepper M.A. Clairmont K.B. Perregaux S.B. Czech M.P. J. Biol. Chem. 1989; 264: 3256-3261Abstract Full Text PDF PubMed Google Scholar, 18Xu Y. Papageorgiou A. Polychronakos C. J. Clin. Endocrinol. Metab. 1998; 83: 437-442PubMed Google Scholar, 19Valenzano K.J. Remmler J. Lobel P. J. Biol. Chem. 1995; 270: 16441-16448Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). There is evidence that sIGF2R is a biologically active molecule. First, sIGF2R can inhibit DNA synthesis induced by IGF-II and epidermal growth factor in cultured rat hepatocytes (20Scott C.D. Ballesteros M. Madrid J. Baxter R.C. Endocrinology. 1996; 137: 873-878Crossref PubMed Scopus (25) Google Scholar). Second, we have obtained transgenic mice expressing a soluble IGF2R by deletion of the transmembrane domain sequence (sΔIgf2r) and fused to the regulatory sequence of the keratin 10 promoter to target expression to the alimentary canal, skin, and uterus (K10sΔIgf2r transgene). Two lines of K10sΔIgf2r transgenic mice (Kipps and Krishna) showed a 9–20% reduction of wet weight, dry weight, and water content in the alimentary canal. The effects of sΔIGF2R expression were mainly local, because the organs negative for transgene expression were only marginally affected (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The interpretation of the biological activity of sIGF2R is complicated by the heterogeneity of its ligands. To understand to what extent the biological activity of sΔIGF2R is due to interaction with IGF-II, we crossed K10sΔIgf2r transgenics by the following genetically modified mice: 1) transgenics expressing aK10Igf2 minigene and showing local organomegaly (Blast line; Ref. 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). If sΔIGF2R acts by reducing the activity of IGF-II, double transgenics Blast and K10sΔIgf2r should show an attenuation of organomegaly compared with Blast. 2) mice in which the paternal (active) allele of the Igf2 gene is disrupted (Igf2 +/p− ).Igf2 m+/p− mice show a growth deficiency phenotype and are fertile (23DeChiara T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google Scholar). If sΔIGF2R acts exclusively by interacting with IGF-II, organ size should affected in K10sΔIgf2r transgenics that are m+/p− compared m+/p− The of the present the of organ size reduction by the soluble K10sΔIgf2r and Krishna) transgenic mice a Igf2r cDNA in which the sequence the transmembrane domain deleted to a soluble polypeptide The cDNA is the of the keratin 10 promoter is the expressing transgene at and is the expressing line; phenotype in (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). and Igf2 m+/p− mice have A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar, T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google Scholar). mice in this were as and Igf2 in a as the were a a In the K10sΔIgf2r transgene because Blast are and the disrupted of the Igf2 gene to A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar, T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google Scholar). There is evidence that the phenotype of mice is by the of the which the by DNA by to or S. 1996; 12: Full Text PDF PubMed Scopus Google Scholar). The following were 1) and and the of the Igf2r cDNA the The K10sΔIgf2r transgene produced a The were for for 2 and for 2 for 2) to a sequence to the of the keratin 10 and to the of in the Igf2 The were for for 2 and for 2 for transgene produced a and to in the The were for 1 and for for gene produced a Analysis of organ in mice produced by (Kipps line) by m+/p− and mice were by and and the wet of organs of and The of the alimentary were by in by in were in the to wet loss due to organ in or three and the were it to the organ dry weight, water and protein content different dry were at for protein by the in 10 DNA content in the the following of to and C. K. Biochem. PubMed Scopus Google Scholar). wet were obtained by the obtained for a part by the of that by the organ wet to the for the water content by the dry the wet water content by the dry to the water dry were by of of mice for and The number of in in some than the number of in of The that in only mice that were and this frequently a of of the the of the phenotype for in the the of the phenotype that in and of organs the and K10sΔIgf2r in dry dry dry in are in type overexpressing a transgene Blast and double transgenics overexpressing the the and in are the number of of are for with type and were by of and in dry in a of organs expressing the dry dry and of dry in a and of organs expressing the K10sΔIgf2r in dry dry in are in type mice carrying a disrupted paternal Igf2 allele (Igf2 carrying a K10sΔIgf2r transgene and mice with (Kipps and in are the number of is by the of of with type m+/p− and were by of and a is the the of in and the of in organ wet weight, compared with of 1 that organ size is than in dry in a of organs expressing the K10sΔIgf2r dry soluble and of dry soluble in a are in type overexpressing a transgene Blast and double transgenics overexpressing the the and in are the number of of are for with type and were by of and and of are in type mice carrying a disrupted paternal Igf2 allele (Igf2 carrying a K10sΔIgf2r transgene and mice with (Kipps and in are the number of is by the of of with type m+/p− and were by of and a is the the of in and the of in organ wet weight, compared with of 1 that organ size is than and of Igf2 by 1 of by the to the cDNA by the and in of the Igf2 gene and a 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google and To for in and for the cDNA were in the The for were for for 2 and for 2 for were in a and with To whether the soluble receptor growth by excess local IGF-II, were crossed the The of by the keratin 10 and of organ expression The to double transgenics mice with or the other of the The phenotype of the transgenic is to the base for with the double transgenic mice expressing the Igf2 gene the of the keratin 10 promoter (Blast showed local organ as A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). wet in the alimentary canal, skin, and uterus compared with whereas wet in organs negative for transgene expression A in and dry a in the organs A and of water content to dry content shown in mice with of IGF-II T. Eggenschwiler J. Fisher P. D'Ercole A.J. Davenport M.L. Efstradiatis A. Dev. Biol. 1996; 177: 517-535Crossref PubMed Scopus (406) Google Scholar). The water content to dry in Blast in organs A and DNA and protein in of the organs with the of the as A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). In this organ the DNA content by a extent as wet and dry A The phenotype of mice a reduced wet of the alimentary (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The of the Blast to the extent of organomegaly in double transgenics with type and the phenotype of mice in the of the m+/p− the in and In the double the soluble receptor transgene in the as the transgene that excess IGF-II A reduction of organomegaly in most of the organs the wet reduced in double transgenics compared with Blast in the alimentary reduction than in the to in the and and in double transgenics is with the of the expression in the lines (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). In the skin, a reduction of organomegaly only in double transgenics of sΔIGF2R expression the wet of the uterus of the produced a in organ dry with the in wet and DNA content or protein content The in dry in than in transgenics DNA content reduced in the and in compared with Blast in the organ in the which the transgene carrying a paternal allele (Igf2 were than type at in a and were fertile as T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google The of IGF-II and peptide in Igf2 m+/p− mice were the in three independent First, IGF-II in the at 10 by Second, obtained m+/p− mice in a IGF-II as a negative the of the transgenics (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). IGF-II peptide were the of the in an independent in the and of Igf2 m+/p− mice were shown to Igf2 by a in Analysis of organs revealed that the wet of most organs to the of to in and The and the were because wet were in to the of than in organ dry a to wet in the organs whereas in water content to dry weight, DNA or protein and mice showed a reduction of the wet of the and to compared with The and the the only organ expressing the transgene that showed a reduction in size in and The m+/p− and transgenics (Kipps line) with the genetically in different mice revealed that the wet of organs in the alimentary and in the and and wet of the skin, and were in m+/p− and Igf2 m+/p− mice expressing the K10sΔIgf2r transgene (Igf2 m+/p− and Igf2 m+/p− showed a to Igf2 m+/p− mice and than that of type or the organs expressing the the wet and dry of and in of the the following Igf2 m+/p− and the double m+/p− m+/p− the wet of the and were in Igf2 m+/p− mice compared with Igf2 m+/p− and the dry of the with the of the in the and were in Igf2 m+/p− than in Igf2 m+/p− double transgenics in the of the protein content in m+/p− and Igf2 m+/p− of the other organ compared m+/p− organs that the K10sΔIgf2r transgene m+/p− were born at the the or showed high the of or m+/p− and or Igf2 m+/p− 1 Igf2 m+/p− of the of and type or were The membrane form of IGF2R binds IGF-II, retinoic and mannose 6-phosphate (9Kornfeld S. Annu. Rev. Biochem. 1992; 61: 307-330Crossref PubMed Scopus (936) Google Scholar, 10Oka Y. Rozek L.M. Czech M.P. J. Biol. Chem. 1985; 260: 9435-9442Abstract Full Text PDF PubMed Google Scholar, 11Hille-Rehfeld A. Biochim. Biophys. Acta. 1995; 1241: 177-194Crossref PubMed Scopus (218) Google Scholar, 12Dahms N.M. Biochem. Soc. Trans. 1996; 24: 136-141Crossref PubMed Scopus (38) Google Scholar, 13Dennis P.A. Rifkin D.B. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 580-584Crossref PubMed Scopus (460) Google Scholar, 14Kang J.X. Li Y. Leaf A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13671-13676Crossref PubMed Scopus (117) Google Scholar). of ligands as different in and as the form of and lysosomal enzymes and other (9Kornfeld S. Annu. Rev. Biochem. 1992; 61: 307-330Crossref PubMed Scopus (936) Google Scholar). IGF-II is the only ligand of the soluble IGF2R in it is that the of IGF2R a ligand specificity K.J. Remmler J. Lobel P. J. Biol. Chem. 1995; 270: 16441-16448Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). of the of its the biological of sIGF2R are to We a to whether the soluble IGF2R organ size by interacting exclusively with IGF-II. The of mice by transgenics expressing a soluble IGF2R by mice overexpressing IGF-II or carrying a disrupted paternal (active) allele of the Igf2 gene the of and of sIGF2R in If the of the soluble IGF2R growth are solely due to its interaction with IGF-II, the of excess sΔIGF2R should the phenotype of mice that IGF-II (Igf2 m+/p−). to the Igf2 m+/p− mice a phenotype the and in IGF-II that at (23DeChiara T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google Scholar). that IGF-II have effects the size of show that the IGF-II to of the size of the The reduction in of mice as as the T. Eggenschwiler J. Fisher P. D'Ercole A.J. Davenport M.L. Efstradiatis A. Dev. Biol. 1996; 177: 517-535Crossref PubMed Scopus (406) Google Scholar, T.M. Efstradiatis A. Robertson E.J. Nature. 1990; 345: 78-80Crossref PubMed Scopus (1410) Google Scholar). the in the present because we have a in of with mice the F. Graham, We to a in DNA content in of Igf2 m+/p− mice with in which of IGF-II is reduced by of the type 1 IGF receptor show in some In the cellular in the is than in and is in the of Igf2 m+/p− J. Robertson E.J. Efstradiatis A. Full Text PDF PubMed Scopus Google Scholar). The wet of most organs in Igf2 m+/p− mice reduced at and and the and We showed that the of a soluble IGF2R (K10sΔIgf2r and a local reduction in size of the alimentary and the The of expression of the K10sΔIgf2r transgene is by the keratin 10 and it with that of gene at least (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The of the K10sΔIgf2r transgene in the and in a Igf2 m+/p− in in the wet of the Furthermore, the wet of and are different in Igf2 m+/p− and II and We that the soluble IGF2R acts exclusively by reducing the of IGF-II in The of the interaction soluble IGF2R and IGF-II the Blast transgenic which IGF-II in a of organs to sΔIGF2R is in the A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). the of the transgene for 10 the and its phenotype the in First, the wet in the alimentary only in an DNA content in the in compared with Ref. 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). Second, in the content of the to the in II compared with Ref. A. Bates P. Fisher R. Richardson L. Graham C.F. J. Endocrinol. 1994; PubMed Scopus Google Scholar). The of transgenics overexpressing IGF-II the of the keratin 10 promoter line) and of double transgenics revealed that of IGF-II in the and the to organomegaly and that the expression of sΔIGF2R in organs the phenotype of 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar, and 1 and are with the that sΔIGF2R can the of IGF-II. the of the or to the of in the in this with the of expression of the K10sΔIgf2r transgene in the lines (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The wet of the in Igf2 m+/p− mice by compared with the for other organs and the suggesting that IGF-II a in the of the size of the in the is with the that the is to the of IGF-II, the high of transgenic IGF-II in this organ 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar, and The expression of the K10sΔIgf2r transgene in m+/p− in a in the wet of the compared m+/p− and The of this is that sΔIGF2R controls the size of the by that are The of is The only ligands of the membrane form of IGF2R with an growth activity IGF-II are the form of and retinoic acid (1Stewart C.E.H. Rotwein P. Physiol. Rev. 1996; 76: 1005-1026Crossref PubMed Scopus (698) Google P.A. Rifkin D.B. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 580-584Crossref PubMed Scopus (460) Google Scholar). is known whether sIGF2R binds of the ligands and whether it is in the activation of the The high of in that the soluble IGF2R as a of the growth factor that for local activation and growth (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The membrane form of IGF2R binds and the activity of D. Endocrinology. 1996; 137: PubMed Scopus (90) Google Scholar). sIGF2R for to the cellular form of The soluble receptor organ size by the activity of mannose 6-phosphate enzymes that are in the of the Y. Rozek L.M. Czech M.P. J. Biol. Chem. 1985; 260: 9435-9442Abstract Full Text PDF PubMed Google Scholar, 11Hille-Rehfeld A. Biochim. Biophys. Acta. 1995; 1241: 177-194Crossref PubMed Scopus (218) Google Scholar). the wet of the in Igf2 m+/p− mice is than in Igf2 m+/p− whereas the are suggests that receptor that are of IGF-II can with other In that the of of the for IGF-II can the activity of the mannose 6-phosphate in the membrane form of IGF2R R.G. L. Tepper M.A. Czech M.P. A. 1988; PubMed Scopus Google Scholar, W. C.L. Greenstein L.A. Lee L. M.M. Rechler M.M. Nissley S.P. J. Biol. Chem. 1989; 264: Full Text PDF PubMed Google Scholar). A in the sIGF2R molecule. Igf2 m+/p− mice high the A is that the reduced size of the the size of in in the to and in Igf2 m+/p− with the in size of The wet of the to the of the in Igf2 m+/p− mice compared with type wet by following IGF-II the wet of the reduced by the expression of sΔIGF2R in and Igf2 m+/p− it in and the of the phenotype of we that the of of the to sΔIGF2R due to a the size of the organ (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). the shown in the present that the size of the is by IGF-II in Igf2 in Blast and attenuation in in with a factor by sIGF2R in Igf2 m+/p− compared m+/p−). The of sΔIGF2R to the of the uterus in Blast is with the of expression of transgene in this organ (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). The dry and water content to the wet and to other in Igf2 m+/p− mice and in organs overexpressing IGF-II or a soluble IGF2R (21Zaina, S., Newton, R. V. S., Paul, M. R., and Graham, C. F. (1998) Endocrinology, in pressGoogle Scholar). that in most organs a in dry and water content is accompanied by a in DNA or protein that sIGF2R a of with biological of which is IGF-II. is that a of the of IGF-II is a in and protein the that IGF-II (6Wang Z-Q. Fung M, R. Barlow D.P. Wagner E.F. Nature. 1994; 372: 464-467Crossref PubMed Scopus (408) Google Scholar, 7Lau M.M.H. Stewart C.E.H. Liu Z. Bhatt H. Rotwein P. Stewart C.L. Genes Dev. 1994; 8: 2953-2963Crossref PubMed Scopus (475) Google Scholar, 8Ludwig T. Eggenschwiler J. Fisher P. D'Ercole A.J. Davenport M.L. Efstradiatis A. Dev. Biol. 1996; 177: 517-535Crossref PubMed Scopus (406) Google Scholar, 22Ward A. Bates P. Fisher R. Richardson L. Graham C.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10365-10369Crossref PubMed Scopus (90) Google Scholar). The in content to the in dry and involve of following an in the of IGF-II in the with of the The that what is the organ size are The that the growth of the is by the to an and and in J. Endocrinology. 1998; PubMed Scopus Google Scholar, S. A. Endocrinology. 1998; PubMed Scopus Google Scholar). The membrane and soluble of IGF-II, and as of a organ size by the of a must by which IGF-II the at which and are by and by which this is the of IGF-II in the The of this 1) the local expression of a soluble IGF2R the organomegaly induced by excess IGF-II. 2) reduction wet and dry in the alimentary and skin, the DNA content is The soluble IGF2R the size of the and mice IGF-II. suggests that the soluble IGF2R can organ size interactions with IGF-II in mice with IGF-II The soluble IGF2R the size of the mice IGF-II. suggests that the soluble IGF2R can an to the of and of sIGF2R and to the to IGF-II in the of organ size.