An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta.
An oncogenic D842V mutation in the platelet-derived growth factor (PDGF) alpha-receptor (Pdgfra) has recently been described in patients with gastrointestinal stromal tumors. In order to test if the same mutation would confer oncogenic properties to the homologous PDGF beta-receptor (Pdgfrb), the corresponding aspartic acid residue at position 849 of Pdgfrb was changed into valine (D849V) using a knock-in strategy. This mutation turned out to be dominantly lethal and caused death even in chimeras (from 345 transferred chimeric blastocysts, no living coat chimeras were detected). Experiments employing mouse embryonic fibroblasts (MEFs) indicated hyperactivity of the mutant receptor. The mutant receptor was phosphorylated in a ligand-independent manner and, in contrast to wild-type MEFs, mutant cells proliferated even in the absence of ligand. Knockout experiments have previously indicated a role for Pdgfrb in placental development. We therefore analyzed wild-type and Pdgfrb D849V chimeric placentas from different gestational stages. No differences were detected at embryonic days 11.5 and 13.5 (n=4). At embryonic day 17.5, however, chimeric placentas (n=3/4) displayed abnormalities both in the labyrinth and in the chorionic plate. The changes included hyper-proliferation of alpha-smooth muscle actin and platelet/endothelial cell adhesion molecule-1 positive cells in the labyrinth and cells in the chorionic plate. In addition, the fetal blood vessel compartment of the labyrinth was completely disorganized.
Looman
Camilla
C
Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
Sun
Tong
T
Yu
Yang
Y
Zieba
Agata
A
Ahgren
Aive
A
Feinstein
Ricardo
R
Forsberg
Henrik
H
Hellberg
Carina
C
Heldin
Carl-Henrik
CH
Zhang
Xiao-Qun
XQ
Forsberg-Nilsson
Karin
K
Khoo
Nelson
N
Fundele
Reinald
R
Heuchel
Rainer
R
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D020964:Embryo Loss; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D010920:Placenta / Q000002:abnormalities* / Q000098:blood supply / Q000201:enzymology*; D011247:Pregnancy; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism*
D008024:Ligands; D050506:Mutant Chimeric Proteins; D001224:Aspartic Acid; D020797:Receptor, Platelet-Derived Growth Factor beta