Placental Growth Retardation Due to Loss of Imprinting of Phlda2

Mech Dev. 2004 Oct;121(10):1199-210. doi: 10.1016/j.mod.2004.05.017.

Abstract

The maternally expressed/paternally silenced genes Phlda2 (a.k.a. Ipl/Tssc3), Slc22a1l, Cdkn1c, Kcnq1, and Ascl2 are clustered in an imprinted domain on mouse chromosome 7. Paternal deletion of a cis-acting differentially methylated DNA element, Kvdmr1, causes coordinate loss of imprinting and over-expression of all of these genes and the resulting conceptuses show intrauterine growth restriction (IUGR). To test the specific contribution of Phlda2 to IUGR in the Kvdmr1-knockout, we crossed Kvdmr1(+/-) males with Phlda2(+/-) females. Conceptuses with the (Phlda2(+/+); Kvdmr1(+/-)) genotype showed fetal and placental growth retardation. Restoration of Phlda2 dosage to normal, as occurred in the conceptuses with the (Phlda2(-/+); Kvdmr1(+/-)) genotype, had a marginally positive effect on fetal weights and no effect on post-natal weights, but significantly rescued the placental weights. As we previously reported, loss of Phlda2 expression in the wild-type background (Phlda2(-/+); Kvdmr1(+/+) genotype) caused placentomegaly. Thus Phlda2 acts as a true rheostat for placental growth, with overgrowth after gene deletion and growth retardation after loss of imprinting. Consistent with this conclusion, we observed significant placental stunting in BAC-transgenic mice that over-expressed Phlda2 and one flanking gene, Slc22a1l, but did not over-express Cdkn1c.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chromosomes, Artificial, Bacterial / genetics
  • Crosses, Genetic
  • Female
  • Fetal Growth Retardation / genetics
  • Fetal Growth Retardation / pathology
  • Gene Dosage
  • Genomic Imprinting*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology
  • Placenta / abnormalities*
  • Placenta / metabolism
  • Placenta / pathology
  • Pregnancy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Nuclear Proteins
  • RNA, Messenger
  • TSSC3 protein