June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Ift172 conditional knockout mice model human IFT172-associated retinal degeneration
Author Affiliations & Notes
  • Priya Rani Gupta
    Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, United States
    Weill Cornell Medical College, New York, New York, United States
  • Scott H Greenwald
    Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, United States
  • Mihoko Leon
    Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, United States
  • Eric A Pierce
    Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, United States
  • Kinga Maria Bujakowska
    Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Priya Gupta, None; Scott Greenwald, None; Mihoko Leon, None; Eric Pierce, None; Kinga Bujakowska, None
  • Footnotes
    Support  Foundation Fighting Blindness, Research to Prevent Blindness Medical Student Research Fellowship (PRG), Fight for Sight [GA16001(KMB)], National Eye Institute [EY012910 and P30EY014104 (MEEI core support)]
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4520. doi:
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    • Get Citation

      Priya Rani Gupta, Scott H Greenwald, Mihoko Leon, Eric A Pierce, Kinga Maria Bujakowska; Ift172 conditional knockout mice model human IFT172-associated retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4520.

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

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Abstract

Purpose : Intraflagellar transport (IFT) is thought to be critical for building and maintaining photoreceptor outer segments, which can be regarded as specialized sensory cilia. The transition from anterograde to retrograde IFT in photoreceptor outer segments is believed to involve the IFT172 protein, and mutations in the IFT172 gene are associated with phenotypes ranging from isolated retinal degeneration to severe syndromic ciliopathies. The goal of this study was to create a mammalian model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism.

Methods : A rod photoreceptor specific Ift172 knockout mouse model was created by breeding mice carrying a floxed Ift172 allele (Ift172tm1.1Rama designated Ift172loxP) with transgenic mice expressing Cre recombinase under the control of the rhodopsin promoter (Tg(Rho-icre)1Ck; designated iCre+). Ocular coherence tomography (OCT) was used to image the retina and electroretinography (ERG) was used to assess retinal function in mice up to 6 months of age. The wild type Ift172 allele is designated Ift172WT, and wild type mice that do not express Cre recombinase are designated iCre- .

Results : OCT imaging of mice homozygous for the floxed Ift172loxP allele that also express iCre (Ift172loxP/loxP-iCre+) showed thinning of the outer nuclear layer (ONL) beginning at 1 month of age (36±6µm) compared to controls (52±1.5µm). By two months of age, the ONL of the Ift172loxP/loxP-iCre mice had completely degenerated while the control ONL remained full thickness (p<0.01). ERGs generated by Ift172loxP/loxP-iCre+ mice corresponded with OCT data, with diminished retinal function by 1 month of age, and complete absence of function by 3 months of age (p<0.01). No significant changes in OCT or ERG were observed in control mice up to 6 months of age(Ift172loxP/WT-iCre+, Ift172loxP/WT-iCre-, Ift172WT/WT-iCre-, Ift172WT/WT-iCre+, Ift172loxP/loxP-iCre- ). This result is consistent with the recessive inheritance pattern seen in humans.


Conclusions : Ift172loxP/loxP-iCre+ mice accurately model the rapid retinal degeneration observed in patients with IFT172-associated retinal degeneration,. Ift172loxP/loxP-iCre- mice showed no significant ERG or OCT changes, indicating that the presence of two floxed alleles alone does not lead to degeneration. This model can be utilized to gain better understanding IFT172's role in the maintenance of rod photoreceptor outer segments.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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