HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans.
HB-EGF, a member of the EGF family of growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. Here, we show that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function in this process. In developing valves, HB-EGF is synthesized in endocardial cells but accumulates in the mesenchyme by interacting with HSPGs. Disrupting the interaction between HB-EGF and HSPGs in an ex vivo model of endocardial cushion explants resulted in increased mesenchymal cell proliferation. Moreover, homozygous knock-in mice (HB(Delta)(hb/)(Delta)(hb)) expressing a mutant HB-EGF that cannot bind to HSPGs developed enlarged cardiac valves with hyperproliferation of mesenchymal cells; this resulted in a phenotype that resembled that of Hbegf-null mice. Interestingly, although Hbegf-null mice had abnormal heart chambers and lung alveoli, HB(Delta)(hb/)(Delta)(hb) mice did not exhibit these defects. These results indicate that interactions with HSPGs are essential for the function of HB-EGF, especially in cardiac valve development, in which HB-EGF suppresses mesenchymal cell proliferation.
Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. riwamoto@biken.osaka-u.ac.jp
Ryo
R
Iwamoto
Naoki
N
Mine
Taichiro
T
Kawaguchi
Seigo
S
Minami
Kazuko
K
Saeki
Eisuke
E
Mekada
D000818:Animals; D049109:Cell Proliferation; D054089:Endocardial Cushions / Q000378:metabolism*; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice
C587884:Hbegf protein, mouse; D019812:Heparan Sulfate Proteoglycans; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins