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bioRxiv · 10.1101/210617

Ift172 conditional knockout mice exhibit rapid retinal degeneration and protein trafficking defects

Gupta, P. R.·Pendse, N.·Greenwald, S. H.·Leon, M.·Liu, Q.·Pierce, E. A.·Bujakowska, K. M.
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Abstract

Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outer-segments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography responses by one month and complete outer-nuclear layer degeneration by two months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outer-segments proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This murine model recapitulates the retinal phenotype seen in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.

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Gupta, P. R., Pendse, N., Greenwald, S. H., Leon, M., Liu, Q., Pierce, E. A., Bujakowska, K. M.. 2017-10-29. Ift172 conditional knockout mice exhibit rapid retinal degeneration and protein trafficking defects. https://doi.org/10.1101/210617

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