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Gene Review

Igf2r  -  insulin-like growth factor 2 receptor

Mus musculus

Synonyms: 300 kDa mannose 6-phosphate receptor, AI661837, CD222, CI Man-6-P receptor, CI-MPR, ...
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Disease relevance of Igf2r

  • Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements [1].
  • These data show that the biological function of imprinting Igf2r is to increase birth weight and they also establish Igf2r as the Tme gene [2].
  • Mouse mutants inheriting maternally a targeted disruption of the imprinted Igf2r gene, which is normally expressed only from the maternal allele, have increased serum and tissue levels of IGF-II and exhibit overgrowth (135% of normal birthweight) and generalized organomegaly, kinky tail, postaxial polydactyly, heart abnormalities, and edema [3].
  • In one mouse line transgenic for the DNA of bacteriophage lambda, hypermethylation was observed in the imprinted Igf2r gene in DNA from heart muscle [4].
  • Two mouse lines transgenic for an adenovirus promoter-indicator gene construct showed hypomethylation in the interleukin 10 and Igf2r loci [4].

High impact information on Igf2r

  • At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele [5].
  • We investigated the allele-specific expression pattern of the Mas gene on the basis of its proximity to the known imprinted gene for the insulin growth factor type II receptor (Igf2r) [6].
  • The mouse insulin-like growth factor type 2 receptor (Igf2r) is imprinted and expressed exclusively from the maternally inherited chromosome [7].
  • The apparent nonequivalence of the Igf2r gene and Tme results in occurrence of viable mice lacking an active Igf2r gene [8].
  • Here we show that a DMR in the imprinted Igf2r gene (which encodes the receptor for insulin-like growth factor type-2) that has been shown to be necessary for imprinting includes a 113-base-pair sequence that constitutes a methylation imprinting box [9].

Chemical compound and disease context of Igf2r


Biological context of Igf2r


Anatomical context of Igf2r


Associations of Igf2r with chemical compounds

  • Igf2, H19 and Igf2r were all appropriately expressed in the PGES derived cells following induction of differentiation in vitro with all-trans retinoic acid or DMSO, when compared with control (D3) and androgenetic ES cells (AGES) [17].
  • Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene [18].
  • Murine embryos that inherit a nonfunctional insulin-like growth factor-II/cation-independent mannose 6-phosphate receptor (Igf2r) gene from their fathers are viable and develop normally into adults [19].
  • The insulin-like growth factor type 2 receptor, also known as the cation independent mannose-6-phosphate receptor (Igf2r) is an imprinted gene, which is repressed on the paternally inherited allele in midgestation mouse embryos [20].
  • In addition, we have identified mutations in the expressed allele of the M6p/Igf2r in 40% of diethylnitrosamine-initiated rat liver tumors [21].

Physical interactions of Igf2r

  • Ligands precipitated by the CD-MPR appeared identical to those bound by the CI-MPR, with apparent affinity constants ranging between 7 and 28 nM [22].
  • Thus, phosphomannosyl ligands bound to the IGF-II/Man-6-P receptor decrease both IGF-II-binding affinity and IGF-II-receptor cross-linking efficiency [23].

Regulatory relationships of Igf2r

  • Imprinting of the maternally-expressed Igf2r gene is controlled by an intronic imprint control element (ICE) known as Region2 that contains the promoter of the noncoding Air RNA, whose transcript overlaps the silenced paternal Igf2r promoter in an antisense orientation [24].
  • Treatment of cultured fibroblasts with the histone deacetylase inhibitor Trichostatin A induces partial relaxation of genomic imprinting as well as decreased DNA methylation of both Igf2r sense and antisense promoters [25].
  • This indicates, contrary to expectation, that the Airn ncRNA induces imprinted Igf2r expression not by silencing the paternal Igf2r promoter, but by generating an expression bias between the two parental alleles [26].

Other interactions of Igf2r

  • Therefore Igf2r is imprinted and closely linked or identical to Tme [27].
  • The Igf2r and Snrpn genes were activated by the early 4-cell stage and exhibited biallelic and monoallelic expression, respectively, throughout preimplantation development [14].
  • Alterations included loss of methylation with biallelic expression of U2af1-rs1, maternal methylation and predominantly maternal expression of Igf2, and biallelic methylation and expression of Igf2r [28].
  • While IGF signaling is mediated by the type 1 IGF receptor (IGF1R), the type 2 receptor (IGF2R/CI-MPR) serves IGF-II turnover [3].
  • Day 9.5 fetuses that have developed normally revealed only hypermethylated alleles in the H19 differently methylated region (DMR), and both hyper- and hypomethylated alleles in the Igf2r DMR2 [29].

Analytical, diagnostic and therapeutic context of Igf2r


  1. Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements. Pauler, F.M., Stricker, S.H., Warczok, K.E., Barlow, D.P. Genome Res. (2005) [Pubmed]
  2. Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice. Wutz, A., Theussl, H.C., Dausman, J., Jaenisch, R., Barlow, D.P., Wagner, E.F. Development (2001) [Pubmed]
  3. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Ludwig, T., Eggenschwiler, J., Fisher, P., D'Ercole, A.J., Davenport, M.L., Efstratiadis, A. Dev. Biol. (1996) [Pubmed]
  4. Foreign DNA integration. Genome-wide perturbations of methylation and transcription in the recipient genomes. Müller, K., Heller, H., Doerfler, W. J. Biol. Chem. (2001) [Pubmed]
  5. Trans allele methylation and paramutation-like effects in mice. Herman, H., Lu, M., Anggraini, M., Sikora, A., Chang, Y., Yoon, B.J., Soloway, P.D. Nat. Genet. (2003) [Pubmed]
  6. Parental imprinting of the Mas protooncogene in mouse. Villar, A.J., Pedersen, R.A. Nat. Genet. (1994) [Pubmed]
  7. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Stöger, R., Kubicka, P., Liu, C.G., Kafri, T., Razin, A., Cedar, H., Barlow, D.P. Cell (1993) [Pubmed]
  8. Genetic analysis of genomic imprinting: an Imprintor-1 gene controls inactivation of the paternal copy of the mouse Tme locus. Forejt, J., Gregorová, S. Cell (1992) [Pubmed]
  9. The imprinting box of the mouse Igf2r gene. Birger, Y., Shemer, R., Perk, J., Razin, A. Nature (1999) [Pubmed]
  10. Insulin-like growth factor II inhibits glucose-induced insulin exocytosis. Zhang, Q., Berggren, P.O., Larsson, O., Hall, K., Tally, M. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  11. Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: mediated by the mannose-6-phosphate/IGF-II receptor? Dabrosin, C., Johansson, A.C., Ollinger, K. Breast Cancer Res. Treat. (2004) [Pubmed]
  12. Imprinted expression of the Igf2r gene depends on an intronic CpG island. Wutz, A., Smrzka, O.W., Schweifer, N., Schellander, K., Wagner, E.F., Barlow, D.P. Nature (1997) [Pubmed]
  13. Igf2r and Igf2 gene expression in androgenetic, gynogenetic, and parthenogenetic preimplantation mouse embryos: absence of regulation by genomic imprinting. Latham, K.E., Doherty, A.S., Scott, C.D., Schultz, R.M. Genes Dev. (1994) [Pubmed]
  14. Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanisms. Szabó, P.E., Mann, J.R. Genes Dev. (1995) [Pubmed]
  15. Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. Yamasaki, Y., Kayashima, T., Soejima, H., Kinoshita, A., Yoshiura, K., Matsumoto, N., Ohta, T., Urano, T., Masuzaki, H., Ishimaru, T., Mukai, T., Niikawa, N., Kishino, T. Hum. Mol. Genet. (2005) [Pubmed]
  16. Disruption of primary imprinting during oocyte growth leads to the modified expression of imprinted genes during embryogenesis. Obata, Y., Kaneko-Ishino, T., Koide, T., Takai, Y., Ueda, T., Domeki, I., Shiroishi, T., Ishino, F., Kono, T. Development (1998) [Pubmed]
  17. A functional analysis of imprinting in parthenogenetic embryonic stem cells. Allen, N.D., Barton, S.C., Hilton, K., Norris, M.L., Surani, M.A. Development (1994) [Pubmed]
  18. Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene. Schweifer, N., Valk, P.J., Delwel, R., Cox, R., Francis, F., Meier-Ewert, S., Lehrach, H., Barlow, D.P. Genomics (1997) [Pubmed]
  19. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Lau, M.M., Stewart, C.E., Liu, Z., Bhatt, H., Rotwein, P., Stewart, C.L. Genes Dev. (1994) [Pubmed]
  20. Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo. Lerchner, W., Barlow, D.P. Mech. Dev. (1997) [Pubmed]
  21. Imprinted M6p/Igf2 receptor is mutated in rat liver tumors. Mills, J.J., Falls, J.G., De Souza, A.T., Jirtle, R.L. Oncogene (1998) [Pubmed]
  22. Ligand binding specificities of the two mannose 6-phosphate receptors. Sleat, D.E., Lobel, P. J. Biol. Chem. (1997) [Pubmed]
  23. Mannose-6-phosphate enhances cross-linking efficiency between insulin-like growth factor-II (IGF-II) and IGF-II/mannose-6-phosphate receptors in membranes. MacDonald, R.G. Endocrinology (1991) [Pubmed]
  24. Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Zwart, R., Sleutels, F., Wutz, A., Schinkel, A.H., Barlow, D.P. Genes Dev. (2001) [Pubmed]
  25. Allele-specific histone acetylation accompanies genomic imprinting of the insulin-like growth factor II receptor gene. Hu, J.F., Pham, J., Dey, I., Li, T., Vu, T.H., Hoffman, A.R. Endocrinology (2000) [Pubmed]
  26. An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias. Latos, P.A., Stricker, S.H., Steenpass, L., Pauler, F.M., Huang, R., Senergin, B.H., Regha, K., Koerner, M.V., Warczok, K.E., Unger, C., Barlow, D.P. Development (2009) [Pubmed]
  27. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Barlow, D.P., Stöger, R., Herrmann, B.G., Saito, K., Schweifer, N. Nature (1991) [Pubmed]
  28. Altered imprinted gene methylation and expression in completely ES cell-derived mouse fetuses: association with aberrant phenotypes. Dean, W., Bowden, L., Aitchison, A., Klose, J., Moore, T., Meneses, J.J., Reik, W., Feil, R. Development (1998) [Pubmed]
  29. Disruption of imprinting in cloned mouse fetuses from embryonic stem cells. Ogawa, H., Ono, Y., Shimozawa, N., Sotomaru, Y., Katsuzawa, Y., Hiura, H., Ito, M., Kono, T. Reproduction (2003) [Pubmed]
  30. The soluble type 2 insulin-like growth factor (IGF-II) receptor reduces organ size by IGF-II-mediated and IGF-II-independent mechanisms. Zaina, S., Squire, S. J. Biol. Chem. (1998) [Pubmed]
  31. Serum factors alter the extent of dephosphorylation of ligands endocytosed via the mannose 6-phosphate/insulin-like growth factor II receptor. Einstein, R., Gabel, C.A. J. Cell Biol. (1989) [Pubmed]
  32. Insulin-like growth factor II may play a local role in the regulation of ocular size. Cuthbertson, R.A., Beck, F., Senior, P.V., Haralambidis, J., Penschow, J.D., Coghlan, J.P. Development (1989) [Pubmed]
  33. Cellular response to latent TGF-beta1 is facilitated by insulin-like growth factor-II/mannose-6-phosphate receptors on MS-9 cells. Ghahary, A., Tredget, E.E., Mi, L., Yang, L. Exp. Cell Res. (1999) [Pubmed]
  34. Endocytosed cation-independent mannose 6-phosphate receptor traffics via the endocytic recycling compartment en route to the trans-Golgi network and a subpopulation of late endosomes. Lin, S.X., Mallet, W.G., Huang, A.Y., Maxfield, F.R. Mol. Biol. Cell (2004) [Pubmed]
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