title: A Titin mutation defines roles for circulation in endothelial morphogenesis.
abstract: Morphogenesis of the developing vascular network requires coordinated regulation of an extensive array of endothelial cell behaviors. Precisely regulated signaling molecules such as vascular endothelial growth factor (VEGF) direct some of these endothelial behaviors. Newly forming blood vessels also become subjected to novel biomechanical forces upon initiation of cardiac contractions. We report here the identification of a recessive mouse mutation termed shrunken-head (shru) that disrupts function of the Titin gene. Titin was found to be required for the initiation of proper heart contractions as well as for maintaining the correct overall shape and orientation of individual cardiomyocytes. Cardiac dysfunction in shrunken-head mutant embryos provided an opportunity to study the effects of lack of blood circulation on the morphogenesis of endothelial cells. Without blood flow, differentiating endothelial cells display defects in their shapes and patterns of cell-cell contact. These endothelial cells, without exposure to blood circulation, have an abnormal distribution within vasculogenic vessels. Further effects of absent blood flow include abnormal spatial regulation of angiogenesis and elevated VEGF signaling. The shrunken-head mutation has provided an in vivo model to precisely define the roles of circulation on cellular and network aspects of vascular morphogenesis.
authors.affiliation: Department of Neurology and the Gallo Center, University of California at San Francisco, Emeryville, CA 94608, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: May
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Stewart
authors.forename: Wesley
authors.initials: W
authors.lastname: Chang
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Peterson
mesh_terms: D000818:Animals; D001775:Blood Circulation; D016923:Cell Death; D048429:Cell Size; D002874:Chromosome Mapping; D064211:Connectin; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000002:abnormalities / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015017:Yolk Sac / Q000098:blood supply
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases