The biological role of platelet-derived growth factor (PDGF)-AA in lung morphogenesis was investigated by incubating embryonic lung explants with phosphorothioate antisense PDGF-A oligonucleotides, which decreased PDGF-AA but not PDGF-BB protein content. Antisense PDGF-A oligonucleotides inhibited DNA

Branching morphogenesis of many organs, including lung, has been shown to take place in response to epithelial-mesenchymal tissue interactions (Rudnick, 1933; Wessels, 1977). The molecular signals guiding branching morphogenesis are largely unknown. As branching morphogenesis involves cell proliferation, migration and differentiation, the ontogenic sequence of these events in early lung organogenesis needs to be well coordinated. Polypeptide growth factors are believed to play a vital role in a number of these cellular processes. Platelet-derived growth factor (PDGF) expression studies have implicated PDGF in early embryonic development (Goustin et al., 1985, Mercola et al., 1990). PDGF is a dimeric molecule composed of two distinct but related polypeptides (A and B). The two chains assemble as a heterodimer, PDGF-AB, or as homodimers, PDGF-AA or PDGF-BB (Heldin, 1989). PDGF exerts its effect via specific cell surface receptors. Two types of PDGF receptors, designated α and β, have been characterized (Claesson-Welsh et al., 1988, 1989; Matsui et al., 1989). The PDGF α-receptor binds all three isoforms of PDGF whereas the PDGF β-receptor binds only PDGF-BB with high affinity (Hart et al., 1988; Heldin et al., 1988). The role of PDGFs in the early development of branched organs is unknown. We have previously shown that both PDGF homodimers, AA and BB, and both PDGF receptors (α and β) are present in the early embryonic lung (Han et al.,1992, 1993). To explore the physiological function of PDGFs in embryonic lung development, we have recently performed PDGF-BB loss-of-function studies and found that PDGF-BB is involved in regulating embryonic lung growth but not branching (Souza et al., 1994). To extend these studies, we now report that inhibition of PDGF-AA translation with phosphorothioate antisense PDGF-A oligonucleotides (ON) results in a significant reduction in lung size and branching. As PDGF-A is expressed in the epithelium and the α-receptor in the mesenchyme, these results suggest that PDGF-AA and its receptor influence early lung branching via an epithelial-mesenchymal interaction.