Journal Mobile Options
Table of Contents
Vol. 65, Suppl. 3, 2006
Issue release date: April 2006

Imprinted Genes, Placental Development and Fetal Growth

Fowden A.L. · Sibley C. · Reik W. · Constancia M.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


In mammals, imprinted genes have an important role in feto-placental development. They affect the growth, morphology and nutrient transfer capacity of the placenta and, thereby, control the nutrient supply for fetal growth. In particular, the reciprocally imprinted Igf2–H19 gene complex has a central role in these processes and matches the placental nutrient supply to the fetal nutrient demands for growth. Comparison of Igf2P0 and complete Igf2 null mice has shown that interplay between placental and fetal Igf2 regulates both placental growth and nutrient transporter abundance. In turn, epigenetic modification of imprinted genes via changes in DNA methylation may provide a mechanism linking environmental cues to placental phenotype, with consequences for development both before and after birth. Changes in expression of imprinted genes, therefore, have major implications for developmental programming and may explain the poor prognosis of the infant born small for gestational age and the wide spectrum of adult-onset diseases that originate in utero.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. McMillen IC, Robinson JS: Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85:571–633.
  2. Fowden AL, Forhead AJ: Endocrine mechanisms of intrauterine programming. Reproduction 2004;127:515–526.
  3. Constancia M, Kelsey G, Reik W: Resourceful imprinting. Nature 2004;432:53357.

    External Resources

  4. Tycko B, Morison IM: Physiological functions of imprinted genes. J Cell Physiol 2002;192:245–258.
  5. Miozzo M, Simoni G: The role of imprinted genes in fetal growth. Biol Neonate 2002;81:217–228.
  6. Fowden AL: The insulin-like growth factors and feto-placental growth. Placenta 2003;24:803–812.
  7. Coan PM, Burton GJ, Ferguson-Smith AC: Imprinted genes in the placenta , a review. Placenta 2005;26(suppl A):S10–20.

    External Resources

  8. Takahashi K, Kobayashi T, Kanayama N: p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol Hum Reprod 2000;6:1019–1025.
  9. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W: Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 2002;417:945–948.
  10. Efstratiadis A: Genetics of mouse growth. Int J Dev Biol 1998;42:955–976.
  11. Moore T: Genetic conflict, genomic imprinting and establishment of the epigenotype in relation to growth. Reproduction 2001;122:185–193.
  12. McLaren RJ, Montgomery GW: Genomic imprinting of the insulin-like growth factor 2 gene in sheep. Mamm Genome 1999;10:588–591.
  13. Young LE: Imprinting of genes and the Barker hypothesis. Twin Res 2001;4:307–317.
  14. Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.
  15. Frank D, Fortino W, Clark L, Musalo R, Wang W, Saxena A, Li CM, Reik W, Ludwig T, Tycko B: Placental overgrowth in mice lacking the imprinted gene Ipl. Proc Natl Acad Sci USA 2002;99:7490–7495.
  16. Lee JE, Pintar J, Efstratiadis A: Pattern of the insulin-like growth factor II gene expression during early mouse embryogenesis. Development 1990;110:151–159.
  17. Constancia M, Dean W, Lopes S, Moore T, Kelsey G, Reik W: Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19. Nat Genet 2000;26:203–206.
  18. Redline RW, Chernicky CL, Tan HQ, Ilan J: Differential expression of insulin-like growth factor-II in specific regions of the late (post day 9.5) murine placenta. Mol Reprod Dev 1993;36:121–129.
  19. Han VK, Carter AM: Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals. Placenta 2000;21:289–305.
  20. Constancia M, Angidini E, Sandovici I, Smith P, Smith R, Kelsey G, Dean W, Ferguson-Smith A, Sibley CP, Reik W, Fowden A: Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci USA 2005;102:19219–19224.
  21. Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constancia M: Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci USA 2004;101:8204–8208.
  22. Gardner RL, Squire S, Zaina S, Hills S, Graham CF: Insulin-like growth factor-2 regulation of conceptus composition: effects of the trophectoderm and inner cell mass genotypes in the mouse. Biol Reprod 1999;60:190–195.
  23. Regnault TR, Friedman JE, Wilkening RB, Anthony RV, Hay WW Jr: Fetoplacental transport and utilization of amino acids in IUGR: a review. Placenta 2005;26(suppl A):S52–S62.

    External Resources

  24. Matthews JC, Beveridge MJ, Dialynas E, Bartke A, Kilberg MS, Novak DA: Placental anionic and cationic amino acid transporter expression in growth hormone overexpressing and null IGF-II or null IGF-I receptor mice. Placenta 1999;20:639–650.
  25. Lopez MF, Dikkes P, Zurakowski D, Villa-Komaroff L: Insulin-like growth factor II affects the appearance and glycogen content of glycogen cells in the murine placenta. Endocrinology 1996;137:2100–2108.
  26. Reik W, Constancia M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, Tycko B, Sibley C: Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 2003;547:35–44.
  27. Godfrey KM, Matthews N, Glazier J, Jackson A, Wilman C, Sibley CP: Neutral amino acid uptake by the microvillous plasma membrane of the human placenta is inversely related to fetal size at birth in normal pregnancy. J Clin Endocrinol Metab 1998;83:3320–3326.
  28. McKinnon T, Chakraborty C, Gleeson LM, Chidiac P, Lala PK: Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK. J Clin Endocrinol Metab 2001;86:3665–3674.
  29. Waterland RA, Jirtle RL: Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 2004;20:63–68.
  30. Rees WD, Hay SM, Brown DS, Antipatis C, Palmer RM: Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J Nutr 2000;130:1821–1826.
  31. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC: Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005;135:1382–1386.
  32. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM: Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000;62:1526–1535.
  33. Koshla S, Dean W, Brown DS, Reik W, Feil R: Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod 2001;64:918–926.
  34. Li J, Saunders JC, Fowden AL, Dauncey MJ, Gilmour RS: Transcriptional regulation of insulin-like growth factor-II gene expression by cortisol in fetal sheep during late gestation. J Biol Chem 1998;273:10586–10593.
  35. Fowden AL, Li J, Forhead AJ: Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc 1998;57:113–122.
  36. Ward JW, Wooding FB, Fowden AL: Ovine feto-placental metabolism. J Physiol 2004;554:529–541.
  37. Ain R, Canham LN, Soares MJ: Dexamethasone-induced intrauterine growth restriction impacts the placental prolactin family, insulin-like growth factor-II and the Akt signaling pathway. J Endocrinol 2005;185:253–263.
  38. Thomassin H, Flavin M, Espinas ML, Grange T: Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO J 2001;20:1974–1983.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50