June 2015
Volume 56, Issue 7
ARVO Annual Meeting Abstract  |   June 2015
Mouse models for dissection of CHD7 functions in eye development and the basis of ocular defects in CHARGE Syndrome
Author Affiliations & Notes
  • Philip J Gage
    Ophthal & Vis Science, Univ Michigan-Kellogg Eye Ctr, Ann Arbor, MI
  • Elizabeth Hurd
    University of Michigan, Ann Arbor, MI
  • Donna M Martin
    University of Michigan, Ann Arbor, MI
  • Footnotes
    Commercial Relationships Philip Gage, None; Elizabeth Hurd, None; Donna Martin, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 1483. doi:
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      Philip J Gage, Elizabeth Hurd, Donna M Martin; Mouse models for dissection of CHD7 functions in eye development and the basis of ocular defects in CHARGE Syndrome. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1483.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: CHARGE (ocular coloboma, heart defects, choanal atresia, growth retardation, urogenital hypoplasia, and ear defects) Syndrome is the second-leading cause of deaf-blindness after Usher Syndrome. Heterozygous mutations in CHD7 (Chromodomain-helicase-DNA-binding protein 7) cause CHARGE Syndrome in 70-90% of patients with clinical features. We tested the hypothesis that tissue specific heterozygous and knockout mutant mice provide models for molecularly dissecting CHD7 functions during eye development.

Methods: Immunohistochemistry was used to assess CHD7 expression during early eye development. The conditional Chd7flox allele was mated together with Rx-Cre, Le-Cre, or Foxg1-Cre to generate tissue-specific mutants in the neural ectoderm, surface ectoderm, or both, respectively. Eyes of resulting embryos were examined histologically to determine the effects on eye morphogenesis and domain-specific marker expression.

Results: The neural and surface ectoderm express CHD7 by e9.5, prior to the initiation of eye morphogenesis. Homozygous deletion from both ectodermal layers results in severely dysmorphic eyes lacking discernible optic cup and lens structures. Homozygous deletion from the surface ectoderm alone results in hypomorphic lenses but normal appearing optic cups. Heterozygous deletion from the neural ectoderm alone results in coloboma while homozygous deletion results in severe morphogenic defects to the optic cup. Domains expressing markers consistent with the molecular specification of the optic cup, optic stalk, retina, and pigmented epithelium, and neurons, are identifiable in neural ectoderm knockout animals.

Conclusions: Normal eye development requires CHD7 function in multiple embryonic tissues. Lens development requires CHD7 function in the surface ectoderm while optic cup and stalk morphogenesis require CHD7 function in the neural ectoderm. In contrast, CHD7 does not appear to be absolutely required for specification of the major subdivisions within the neural ectoderm during eye development. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. Collectively, these data indicate that Chd7 mutant mice provide unique models for determining the molecular etiology of ocular defects in CHARGE Syndrome.


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