title: Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects.
abstract: PlexinD1 is a membrane-bound receptor that mediates signals derived from class 3 secreted semaphorins. Although semaphorin signaling in axon guidance in the nervous system has been extensively studied, functions outside the nervous system including important roles in vascular patterning have also been demonstrated. Inactivation of plexinD1 leads to neo-natal lethality, structural defects of the cardiac outflow tract, peripheral vascular abnormalities, and axial skeletal morphogenesis defects. PlexinD1 is expressed by vascular endothelial cells, but additional domains of expression have also been demonstrated including in lymphocytes, osteoblasts, neural crest and the central nervous system. Hence, the cell-type specific functions of plexinD1 have remained unclear. Here, we describe the results of tissue-specific gene inactivation of plexinD1 in Tie2 expressing precursors, which recapitulates the null phenotype with respect to congenital heart, vascular, and skeletal abnormalities resulting in neonatal lethality. Interestingly, these mutants also have myocardial defects not previously reported. In addition, we demonstrate functions for plexinD1 in post-natal retinal vasculogenesis and adult angiogenesis through the use of inducible cre-mediated deletion. These results demonstrate an important role for PlexinD1 in embryonic and adult vasculature.
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.forename: Karl R
authors.initials: KR
authors.lastname: Degenhardt
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003433:Crosses, Genetic; D047108:Embryonic Development; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000196:embryology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C473552:Plxnd1 protein, mouse; D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases