title: Wnt/β-catenin and sonic hedgehog pathways interact in the regulation of the development of the dorsal mesenchymal protrusion.
abstract: BACKGROUND
  The dorsal mesenchymal protrusion (DMP) is a second heart field (SHF) derived tissue involved in cardiac septation. Molecular mechanisms controlling SHF/DMP development include the Bone Morphogenetic Protein and Wnt/β-catenin signaling pathways. Reduced expression of components in these pathways leads to inhibition of proliferation of the SHF/DMP precursor population and failure of the DMP to develop. While the Sonic Hedgehog (Shh) pathway has also been demonstrated to be critically important for SHF/DMP development and atrioventricular septation, its role in the regulation of SHF proliferation is contentious.
  
  
  RESULTS
  Tissue-specific deletion of the Shh receptor Smoothened from the SHF resulted in compromised DMP formation and atrioventricular septal defects (AVSDs). Immunohistochemical analysis at critical stages of DMP development showed significant proliferation defect as well as reduction in levels of the Wnt/β-catenin pathway-intermediates β-catenin, Lef1, and Axin2. To determine whether the defects seen in the conditional Smoothened knock-out mouse could be attributed to reduced Wnt/β-catenin signaling, LiCl, a pharmacological activator of this Wnt/β-catenin pathway, was administered. This resulted in restoration of proliferation and partial rescue of the AVSD phenotype.
  
  
  CONCLUSIONS
  The data presented suggest that the Wnt/β-catenin pathway interact with the Shh pathway in the regulation of SHF/DMP-precursor proliferation and, hence, the development of the DMP.
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Laura E
authors: LE
authors: Briggs
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Tara A
authors: TA
authors: Burns
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Marie M
authors: MM
authors: Lockhart
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Aimee L
authors: AL
authors: Phelps
authors: Heart Failure Research Center, Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors: Maurice J B
authors: MJ
authors: Van den Hoff
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Andy
authors: A
authors: Wessels
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D051176:beta Catenin
keywords: atrioventricular; heart; mouse; proliferation; septal defect