title: Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis.
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 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.
authors.affiliation: Institute of Nutritional Science, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Carbe
authors.affiliation: Institut für Physiologische Chemie und Pathobiochemie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kupich
authors.affiliation: Institut für Physiologische Chemie und Pathobiochemie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Pickhinke
authors.affiliation: Institut für Physiologische Chemie und Pathobiochemie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany; Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ohlig
authors.affiliation: Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Frye
authors.affiliation: Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Seelige
authors.affiliation: Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Pallerla
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Moon
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093-0687, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093-0687, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institut für Physiologische Chemie und Pathobiochemie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany; Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany. Electronic address: kgrobe@uni-muenster.de.
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004310:Double Outlet Right Ventricle / Q000235:genetics; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013348:Subclavian Artery / Q000002:abnormalities; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014339:Truncus Arteriosus, Persistent / Q000235:genetics
chemical_list: D017931:DNA Primers; D051524:Fibroblast Growth Factor 8; D006497:Heparan Sulfate; D015238:Sulfotransferases; C496457:Fgf8 protein, mouse; C021350:heparitin sulfotransferase
keywords: Fibroblast growth factor; Heart development; Heparan sulfate; NDST1; Neural crest