Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A

Abstract

Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxy-terminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-Along has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Δex6)) incapable of producing PDGF-Along due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFRα), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Δex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-Along may play a physiological role.