title: Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin.
abstract: We have examined the role of Furin in postimplantation-stage mouse embryos by analyzing both the expression pattern of fur mRNA and the developmental consequences of a loss-of-function mutation at the fur locus. At early stages (day 7.5), fur mRNA is abundant in extraembryonic endoderm and mesoderm, anterior visceral endoderm, and in precardiac mesoderm. 1 day later fur is expressed throughout the heart tube and in the lateral plate mesoderm, notochordal plate and definitive gut endoderm. Embryos lacking Furin die between days 10.5 and 11.5, presumably due to hemodynamic insufficiency associated with severe ventral closure defects and the failure of the heart tube to fuse and undergo looping morphogenesis. Morphogenesis of the yolk sac vasculature is also abnormal, although blood islands and endothelial precursors form. Analysis of cardiac and endodermal marker genes shows that while both myocardial precursors and definitive endoderm cells are specified, their numbers and migratory properties are compromised. Notably, mutant embryos fail to undergo axial rotation, even though Nodal and eHand, two molecular markers of left-right asymmetry, are appropriately expressed. Overall, the present data identify Furin as an important activator of signals responsible for ventral closure and embryonic turning.
authors.affiliation: Laboratory for Molecular Oncology, Experimental Genetics Group, Center for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology (VIB), Herestraat 49, B-3000 Leuven, Belgium.anton.roebroek@med.kuleuven.ac.be
authors.forename: A J
authors.initials: AJ
authors.lastname: Roebroek
authors.forename: L
authors.initials: L
authors.lastname: Umans
authors.forename: I G
authors.initials: IG
authors.lastname: Pauli
authors.forename: E J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: F
authors.initials: F
authors.lastname: van Leuven
authors.forename: W J
authors.initials: WJ
authors.lastname: Van de Ven
authors.forename: D B
authors.initials: DB
authors.lastname: Constam
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian / Q000201:enzymology; D005314:Embryonic and Fetal Development; D045683:Furin; D050991:GATA4 Transcription Factor; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018390:Gene Targeting; D017930:Genes, Reporter / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism*; D006651:Histocytochemistry; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D055457:Nodal Protein; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D013381:Subtilisins / Q000172:deficiency / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D029867:Xenopus Proteins
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D055457:Nodal Protein; C526008:Nodal protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D013381:Subtilisins; D045683:Furin