title: Defective Angiogenesis and Intraretinal Bleeding in Mouse Models With Disrupted Inner Retinal Lamination.
abstract: OBJECTIVE
  Abnormal retinal angiogenesis leads to visual impairment and blindness. Understanding how retinal vessels develop normally has dramatically improved treatments for people with retinal vasculopathies, but additional information about development is required. Abnormal neuron patterning in the outer retina has been shown to result in abnormal vessel development and blindness, for example, in people and mouse models with Crumbs homologue 1 (CRB1) mutations. In this study, we report and characterize a mouse model of inner retinal lamination disruption and bleeding, the Down syndrome cell adhesion molecule (Dscam) mutant, and test how neuron-neurite placement within the inner retina guides development of intraretinal vessels.
  
  
  METHODS
  Bax mutant mice (increased neuron cell number), Dscam mutant mice (increased neuron cell number, disorganized lamination), Fat3 mutant mice (disorganized neuron lamination), and Dscam gain-of-function mice (Dscam(GOF)) (decreased neuron cell number) were used to manipulate neuron placement and number. Immunohistochemistry was used to assay organization of blood vessels, glia, and neurons. In situ hybridization was used to map the expression of angiogenic factors.
  
  
  RESULTS
  Significant changes in the organization of vessels within mutant retinas were found. Displaced neurons and microglia were associated with the attraction of vessels. Using Fat3 mutant and Dscam(GOF) retinas, we provide experimental evidence that vessel branching is induced at the neuron-neurite interface, but that other factors are required for full plexus layer formation. We further demonstrate that the displacement of neurons results in the mislocalization of angiogenic factors.
  
  
  CONCLUSIONS
  Inner retina neuron lamination is required for development of intraretinal vessels.
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, Idaho, United States.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Simmons
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, Idaho, United States.
authors.forename: Morgan M
authors.initials: MM
authors.lastname: Merrill
authors.affiliation: University of Washington School of Medicine, WWAMI Medical Education Program, Moscow, Idaho, United States.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: University of Utah School of Medicine, Division of Otolaryngology-Head and Neck Surgery, Salt Lake City, Utah, United States 4University of Utah School of Medicine, Department of Neurobiology and Anatomy, Salt Lake City, Utah, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Deans
authors.affiliation: Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, Maryland, United States.
authors.forename: Malia M
authors.initials: MM
authors.lastname: Edwards
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, Idaho, United States 2University of Washington School of Medicine, WWAMI Medical Education Program, Moscow, Idaho, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Fuerst
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D002452:Cell Count; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000378:metabolism; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D012160:Retina / Q000002:abnormalities*; D012166:Retinal Hemorrhage / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D055351:Retinal Neurons / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology; D039961:Semaphorins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494827:Bax protein, mouse; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C491735:Dscam protein, mouse; C518412:Fat3 protein, mouse; D006023:Glycoproteins; D008565:Membrane Proteins; C111150:Sema3e protein, mouse; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; C510203:semaphorin 3C protein, mouse; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2