Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2.
Defects in heart development are the most common congenital abnormalities in humans, providing a strong incentive to learn more about the underlying causes. Previous studies have implicated the metalloprotease-disintegrins ADAMs (a disintegrin and metalloprotease) 17 and 19 as well as heparin binding EGF-like growth factor (HB-EGF) and neuregulins in heart development in mice. Here, we show that mice lacking both ADAMs 17 and 19 have exacerbated defects in heart development compared to mice lacking either ADAM, providing the first evidence for redundant or compensatory functions of ADAMs in development. Moreover, we identified additional compensatory or redundant roles of ADAMs 9 and 19 in morphogenesis of the mitral valve and cardiac outflow tract. Cell biological studies designed to address the functions of these ADAMs in shedding of HB-EGF uncovered a contribution of ADAM19 to this process, but this was only evident in the absence of the major HB-EGF sheddase, ADAM17. In addition, ADAM17 emerged as the major sheddase for neuregulins beta1 and beta2 in mouse embryonic fibroblasts. These results raise the possibility that ADAMs 9, 17, and 19 contribute to heart development in humans and have implications for understanding the mechanisms underlying congenital heart disease.
Horiuchi
Keisuke
K
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.
Zhou
Hong-Ming
HM
Kelly
Kristine
K
Manova
Katia
K
Blobel
Carl P
CP
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002522:Chlorocebus aethiops; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006321:Heart / Q000196:embryology* / Q000254:growth & development*; D006330:Heart Defects, Congenital / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008943:Mitral Valve / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D009206:Myocardium / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014261:Tricuspid Valve / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development
D019483:Disintegrins; C094131:NRG1 protein, human; C106766:NRG2 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D011993:Recombinant Fusion Proteins; D008666:Metalloendopeptidases