Abstract PDGF isoforms are a family of poly- peptides that bind to cell surface receptors and induce fibroblast proliferation and chemotaxis. PDGF-A and -B chain isoforms have previously been shown to be involved in murine lung development. A new PDGF polypeptide, PDGF- C, was recently recognized and differs from the PDGF-A and -B isoforms in that it requires proteolytic cleavage before it can bind and acti- vate the PDGF alpha receptor. In these studies PDGF-C was over-expressed during embryogen- esis using the lung specific surfactant protein C promoter. PDGF-C transgenic pups died from respiratory insufficiency within minutes following birth. At E18.5, nontransgenic lungs exhibited lung morphology consistent with the saccular stage of lung development. In contrast, E18.5 transgenic lungs retained many features of the canalicular stage of lung development and had abundant numbers of large poorly differentiated mesenchymal cells. These results suggest that PDGF-C is activated during lung development and is a potent growth factor for mesenchymal cells in vivo. Keywords Mitogen Æ Mouse Æ PDGF Æ Embryogenesis Æ Development Introduction There are now four known platelet-derived growth factor (PDGF) ligands (A–D) and two cell membrane receptors designated alpha and beta. PDGF-A and -B chains were described over 30 years ago (Raines 1990), whereas the PDGF-C isoform was not reported until 2000 (Li et al. 2000). PDGF-A and -B chains dimerize into ho- modimers, AA and BB, or an AB heterodimer. The ligand dimers bind to cell surface PDGF receptors pairs, and monomers are inactive (Heldin and Westermark 1990a, b). The newly described PDGF-C chain also dimerizes and binds to PDGF-aa and -ab receptor dimers (Cao et al. 2002), but in contrast to PDGF-A and -B, requires proteolytic cleavage for receptor binding (Li et al. 2000). PDGF-C is composed of a signal sequence for secretion, a Complement subcom- ponents Clr/Cls, Uegf, Bmp1 domain (CUB do- main) that may serve to bind the peptide to connective tissue elements within the interstitium, an activation cleavage site, and a receptor-binding cysteine knot that facilitates dimerization through sulfhydryl bonds (Uutela et al. 2001). The importance of PDGF-A and -B chain, as well as both PDGF a and b receptors, in lung Y. Zhuo Æ G. W. Hoyle Æ B. Shan Æ D. R. Levy Æ J. A. Lasky (&) Departments of Medicine and Pathology , Tulane University Health Sciences Center , 1430 Tulane Avenue , New Orleans, LA 70112 , USA e-mail: jlasky@tulane.edu Transgenic Res (2006) 15:543–555 DOI 10.1007/s11248-006-9007-5 123 ORIGINAL PAPER Over-expression of PDGF-C using a lung specific promoter results in abnormal lung development Ying Zhuo Æ Gary W. Hoyle Æ Bin Shan Æ Dawn R. Levy Æ Joseph A. Lasky Received: 26 January 2006 / Accepted: 21 April 2006 / Published online: 9 July 2006 Ó Springer Science+Business Media B.V. 2006