Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis

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• 作者：Yi Pan^a ; Christian Carbe^b ; Sabine Kupich^c ; Ute Pickhinke^c ; Stefanie Ohlig^c ; ^d ; Maike Frye^d ; Ruth Seelige^d ; Srinivas R. Pallerla^d ; Anne M. Moon^e ; ^f ; ^g ; Roger Lawrence^h ; Jeffrey D. Esko^h ; Xin Zhang^b ; Kay Grobe^c ; ^d ; ^{kgrobe@uni-muenster.de" class="auth_mail}
• 关键词：VSD ; Ventricular septal defect ; DORV ; Double outlet right ventricle ; PTA ; Persistent truncus arteriosus ; RERSC ; Retroesophageal right subclavian artery ; NDST ; GlcNAc N-deacetylase/GlcN N-sulfotransferase ; EXT1 ; Exostosin 1 ; NCC ; Neural crest cell ; FGF ; Fibroblast growth factor ; FGFR ; Fibroblast growth factor receptor ; PA ; Pharyngeal arch ; CNC ; Cardiac neural crest ; OFT ; Outflow tract ; HS ; Heparan sulfate ; HSPG ; Heparan sulfate proteoglycan ; MAPK ; Mitogen-activated protein kinase ; ERK ; Extracellu
• 刊名：Matrix Biology
• 出版年：April 2014
• 年：2014
• 卷：35
• 期：Complete
• 页码：253-265
• 全文大小：3190 K

文摘

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 NDST1^−/− 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.