Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8455396 | Matrix Biology | 2014 | 13 Pages |
Abstract
Impaired heparan sulfate (HS) synthesis in vertebrate development causes complex malformations due to the functional disruption of multiple HS-binding growth factors and morphogens. Here, we report developmental heart defects in mice bearing a targeted disruption of the HS-generating enzyme GlcNAc N-deacetylase/GlcN N-sulfotransferase 1 (NDST1), including ventricular septal defects (VSD), persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), and retroesophageal right subclavian artery (RERSC). These defects closely resemble cardiac anomalies observed in mice made deficient in the cardiogenic regulator fibroblast growth factor 8 (FGF8). Consistent with this, we show that HS-dependent FGF8/FGF-receptor2C assembly and FGF8-dependent ERK-phosphorylation are strongly reduced in NDST1â/â embryonic cells and tissues. Moreover, WNT1-Cre/LoxP-mediated conditional targeting of NDST function in neural crest cells (NCCs) revealed that their impaired HS-dependent development contributes strongly to the observed cardiac defects. These findings raise the possibility that defects in HS biosynthesis may contribute to congenital heart defects in humans that represent the most common type of birth defect.
Keywords
FGFRNdstNdst1GlcAEXT1HSPGVSDCNCOFTPTANCCFGFDORVTGFβGlcNAcERKMAPKN-acetyl glucosaminePersistent truncus arteriosusGlucuronic aciddouble outlet right ventricleTransforming Growth Factor BetaHeart developmentneural crest cellfibroblast growth factorneural crestPharyngeal archBMPOutflow tractVentricular septal defectHeparan sulfateHeparan sulfate proteoglycanBone morphogenetic proteinmitogen-activated protein kinaseCardiac neural crestextracellular signal-regulated kinasefibroblast growth factor receptor
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Authors
Yi Pan, Christian Carbe, Sabine Kupich, Ute Pickhinke, Stefanie Ohlig, Maike Frye, Ruth Seelige, Srinivas R. Pallerla, Anne M. Moon, Roger Lawrence, Jeffrey D. Esko, Xin Zhang, Kay Grobe,