title: Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome.
abstract: OBJECTIVE
  CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary tract abnormalities, and Ear abnormalities and deafness) is the second-leading cause of deaf-blindness after Usher syndrome. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients. We tested the hypothesis that tissue-specific mutant mice provide models for molecularly dissecting CHD7 functions during eye development.
  
  
  METHODS
  The conditional Chd7flox allele was mated together with tissue-specific Cre transgenes. Immunohistochemistry was used to determine the normal CHD7 pattern in the early eye primordia and to assess Chd7 mutants for expression of region-specific protein markers.
  
  
  RESULTS
  CHD7 is present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm results in severely dysmorphic eyes generally lacking recognizable optic cup structures and small lenses. Deletion from the neural ectoderm results in similar defects. Deletion from the surface ectoderm results in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm are present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depends on the Chd7 gene dose within the neural ectoderm.
  
  
  CONCLUSIONS
  Eye development requires CHD7 in multiple embryonic tissues. Lens development requires CHD7 in the surface ectoderm, whereas optic cup and stalk morphogenesis require CHD7 in the neural ectoderm. CHD7 is not absolutely required for specification of the major subdivisions within the neural ectoderm. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. These data indicate the Chd7 mutant mice are models for determining the molecular etiology of ocular defects in CHARGE syndrome.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Michigan Medical School, Ann Arbor, Michigan, United States 2Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gage
authors.affiliation: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hurd
authors.affiliation: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, United States 4Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
mesh_terms: D000483:Alleles; D000818:Animals; D058747:CHARGE Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D038081:Organogenesis; D011247:Pregnancy; D011270:Pregnancy, Animal
chemical_list: D015820:Cadherins; C501012:Cdh7 protein, mouse; D004247:DNA