PDGF-A/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis.
Platelet-derived growth factors (PDGF) constitute a family of four gene products (PDGF-A-D) acting by means of two receptor tyrosine kinases, PDGFR alpha and beta. Three of the ligands (PDGF-A, -B, and -C) bind to PDGFR alpha with high affinity. Knockout of pdgf-a in mice has demonstrated a role for PDGF-A in the recruitment of smooth muscle cells to the alveolar sacs and their further compartmentalization into alveoli. Although this is a late, postnatal step in lung development, pdgf-a antisense oligonucleotides were previously shown to inhibit epithelial branching in rat lung explants in vitro, which reflects an early embryonic process. These conflicting results may be explained by substitution of genetic loss of pdgf-a by maternal transfer of PDGF-A to the knockout embryo or the presence of other PDGFR alpha agonists (PDGF-B and -C) in vivo, potentially masking an effect of PDGF-A on branching morphogenesis. Alternatively, the administration of pdgf-a antisense oligonucleotides affected other processes than the intended. To discriminate between these opposing possibilities, we have analyzed lung development in pdgfr alpha -/- embryos and lung primordia grown in vitro. Our analysis shows that, while the pdgfr alpha -/- lungs and explanted lung rudiments were smaller than normal, branching morphogenesis appears qualitatively intact and proceeds until at least embryonic day 15.5, generating both prospective conducting and respiratory airways. We conclude that, although PDGF-AA signaling over PDGFR alpha may have direct or indirect roles in overall lung growth, it does not specifically control early branching of the lung epithelium.
Boström
Hans
H
Department of Medical Biochemistry, Göteborg University, Göteborg, Sweden. hans.bostrum@medkem.gu.se
Gritli-Linde
Amel
A
Betsholtz
Christer
C
D000818:Animals; D008168:Lung / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009924:Organ Culture Techniques; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha