Essential Role for ADAM19 in Cardiovascular Morphogenesis

Abstract

Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19 ؊/؊ animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects.ADAMs (mnemonic for a disintegrin and metalloprotease) are membrane-anchored glycoproteins with key roles in fertilization, neurogenesis, angiogenesis, Alzheimer's disease, and the release of proteins such as epidermal growth factor (EGF) receptor ligands and tumor necrosis factor family members from the plasma membrane (3,4,17,37,39,41). ADAM19 (also referred to as meltrin ␤) was initially identified in muscle cells and was later found to be expressed in several other tissues, most prominently in heart, lung, and bone (18, 27, 52), during dendritic cell differentiation (13) and Notch-induced T-cell maturation (9). The catalytic activity of ADAM19 towards candidate substrates has been explored by overexpression in cells and by purifying recombinantly expressed soluble forms of the entire ectodomain or the pro-and metalloprotease domains (7,42,49,53). Overexpressed ADAM19 enhances ectodomain shedding of two of several splice variants of neuregulin I-␤ (42), a ligand for the ErbB family of receptor tyrosine kinases (11). Furthermore, overexpression of ADAM19 increases ectodomain release of tumor necrosis factor-related activation-induced cytokine (TRANCE, also referred to as osteoprotegerin-ligand [OPGL]) (7), a protein with important roles in osteoclast differentiation, dendritic cell survival, and mammary gland development (12,25,28).In light of the high expression of ADAM19 in heart and bone and its ability to cleave TRANCE as well as splice variants of neuregulin I-␤, we were interested in evaluating the function of ADAM19 in mice, with an emphasis on its role in heart and bone development. Here we present an analysis of mice lacking functional ADAM19 (adam19 Ϫ/Ϫ mice). MATERIALS AND METHODS Generation of adam19؊/؊ mice. adam19 ϩ/Ϫ mice were generated by the SloanKettering Institute transgenic facility by following standard procedures using stem cells with a secretory gene trap insertion in ADAM19 (30). All mice evaluated in this study were of mixed genetic background (129Sv/C57BL6), and morphological and hist...

Dnmt3l-knockout donor cells improve somatic cell nuclear transfer reprogramming efficiency

“…5B). In addition, we found that the expression levels of several genes associated with embryonic development, including Adam19, Chd8, Git1, Lims1/Pinch1, Pogz and Sulf1, were increased in Dnmt3l-KO MEFs (Nishiyama et al 2004, Zhou et al 2004, Liang et al 2005, Holst et al 2007, Pang et al 2009). We further investigated the DNA methylation state of CpG islands in the promoter regions of three differentially expressed genes Adam19, Git1 and Lims1.…”

Upregulation of ADAM19 in Chronic Allograft Nephropathy

“…Experiments in ADAM19 knockout mice showed that ADAM19 is possibly involved in the vascular ensheathment of smooth muscle cells (20 (3,26). The RGD containing disintegrin functions as an adhesion molecule that mediates cellcell interaction via alphavb3 (27).…”

“…Studies in monocytes suggest that ADAM19 is important for early adhesion and migration from the blood into peripheral tissue (8). Furthermore, genetic inactivation of ADAM19 in mice resulted in perinatal death due to severe cardiac dysfunction (20,21).…”

Probing cellular microenvironments and tissue remodeling by atomic force microscopy

“…ADAMs are currently emerging as the major mediators of ectodomain shedding (for example [80,124]). Besides their relevance to inflammatory diseases and cancer, ADAMs are putative key regulators of morphogenesis (for example, [3,70,178]). …”