title: Loss of function of parathyroid hormone receptor 1 induces Notch-dependent aortic defects during zebrafish vascular development.
abstract: OBJECTIVE
  Coarctation of the aorta is rarely associated with known gene defects. Blomstrand chondrodysplasia, caused by mutations in the parathyroid hormone receptor 1 (PTHR1) is associated with coarctation of the aorta in some cases, although it is unclear whether PTHR1 deficiency causes coarctation of the aorta directly. The zebrafish allows the study of vascular development using approaches not possible in other models. We therefore examined the effect of loss of function of PTHR1 or its ligand parathyroid hormone-related peptide (PTHrP) on aortic formation in zebrafish.
  
  
  RESULTS
  Morpholino antisense oligonucleotide knockdown of either PTHR1 or PTHrP led to a localized occlusion of the mid-aorta in developing zebrafish. Confocal imaging of transgenic embryos showed that these defects were caused by loss of endothelium, rather than failure to lumenize. Using a Notch reporter transgenic ([CSL:Venus]qmc61), we found both PTHR1 and PTHrP knockdown-induced defective Notch signaling in the hypochord at the site of the aortic defect before onset of circulation, and the aortic occlusion was rescued by inducible Notch upregulation.
  
  
  CONCLUSIONS
  Loss of function of either PTHR1 or PTHrP leads to a localized aortic defect that is Notch dependent. These findings may underlie the aortic defect seen in Blomstrand chondrodysplasia, and reveal a link between parathyroid hormone and Notch signaling during aortic development.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gray
authors.forename: David
authors.initials: D
authors.lastname: Bratt
authors.forename: Julie
authors.initials: J
authors.lastname: Lees
authors.forename: Marc
authors.initials: M
authors.lastname: daCosta
authors.forename: Karen
authors.initials: K
authors.lastname: Plant
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Watson
authors.forename: Sara
authors.initials: S
authors.lastname: Solaymani-Kohal
authors.forename: Simon
authors.initials: S
authors.lastname: Tazzyman
authors.forename: Jovana
authors.initials: J
authors.lastname: Serbanovic-Canic
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Keavney
authors.forename: Andrea
authors.initials: A
authors.lastname: Haase
authors.forename: Kathryn
authors.initials: K
authors.lastname: McMahon
authors.forename: Martin
authors.initials: M
authors.lastname: Gering
authors.forename: Henry
authors.initials: H
authors.lastname: Roehl
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
authors.forename: Timothy J A
authors.initials: TJ
authors.lastname: Chico
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology*; D001017:Aortic Coarctation / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D012016:Reference Values; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051881:Receptor, Notch1; D044168:Receptor, Parathyroid Hormone, Type 1; D029961:Zebrafish Proteins; C437805:notch1a protein, zebrafish
keywords: angiogenesis; aortic coarctation; parathyroid hormone; zebrafish