Int. J. Dev. Biol. 51: 361 - 370 (2007)

https://doi.org/10.1387/ijdb.072301cl

Vol 51, Issue 5

An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta

Original Article | Published: 27 June 2007

Camilla Looman¹, Tong Sun², Yang Yu², Agata Zieba¹, Aive Ahgren¹, Ricardo Feinstein³, Henrik Forsberg¹, Carina Hellberg¹, Carl-Henrik Heldin¹, Xiao-Qun Zhang⁴, Karin Forsberg-Nilsson⁴, Nelson Khoo⁵, Reinald Fundele² and Rainer Heuchel^1,*

¹Ludwig Institute for Cancer Research, Uppsala University, ²Department of Development and Genetics, Uppsala University, ³National Veterinary Institute, ⁴Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden and Umeå Biotech Incubator, Umeå, Sweden

Abstract

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.

Keywords

gene targeting, pericyte, labyrinthine layer, growth factor signaling