Placental growth retardation due to loss of imprinting of Phlda2.
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.
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
Martha
M
Salas
Rosalind
R
John
Anjana
A
Saxena
Sheila
S
Barton
Dale
D
Frank
Galina
G
Fitzpatrick
Michael J
MJ
Higgins
Benjamin
B
Tycko
D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000473:pathology; D018628:Gene Dosage; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D010920:Placenta / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D009687:Nuclear Proteins; D012333:RNA, Messenger; C109277:TSSC3 protein