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Tanya Dilan, Ratnesh Singh, Thamaraiselvi Saravanan, Andrew F X Goldberg, Visvanathan Ramamurthy; Bardet-Biedl syndrome-8 (BBS8) is essential for morphogenesis of photoreceptor outer segments. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2052. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Bardet-Biedl Syndrome complex (BBSome) is a multiprotein complex linked to retinitis pigmentosa, yet its role in photoreceptors remains poorly understood. It is thought that the BBSome is important for ciliogenesis and it has also been linked to anterograde protein trafficking. However, recent studies have questioned these findings in photoreceptors. The purpose of this study is to tease out the molecular mechanisms underlying the photoreceptor pathology in Bardet-Biedl Syndrome. We have generated multiple animal models lacking BBS8, a core component of the BBSome, focusing on identifying the role of BBS8 in vision.
To study the role of BBS8/BBSome in photoreceptors, we generated four different animal models:1)A global knockout, 2)Retina-specific conditional, 3)Cone-photoreceptor specific conditional and 4)Lastly, to investigate the role of BBS8 in maintenance of photoreceptors, a rod-specific inducible knockout was generated. Retinal morphology was examined by light- and electron microscopy. Protein expression and subcellular localization were analyzed by immunoblotting and immunocytochemistry, respectively.
Ultrastructural analysis of our global knockout mice revealed dysmorphic photoreceptor outer segments at early stages of photoreceptor development (postnatal day 10-P10). Interestingly, at P10, exo-vesicles were abundant in the extracellular space. Cone-specific model revealed the need for BBS8 in survival and function of cone photoreceptors. Additionally, in the absence of BBS8, we observed dynamic changes of other BBS partner subunits. Ablation of BBS8 led to the accumulation of Syntaxin3 (STX3), a protein normally found in the IS and synapse, in the rod OS at P10. Interestingly, cone-specific deletion of BBS8 led to a similar accumulation of STX3 in the cone OS, prior to defects in cone function (Fig 1).
Our results show the need for BBS8 in development of photoreceptor outer segments. In comparison to other animal models for BBS, removal of BBS8 results in early and severe dysmorphogenesis of the OS. It is not clear if the observed accumulation of STX3 contributes to the photoreceptor pathology and/or is the byproduct of defective photoreceptor morphology. Our current efforts are focused on distinguishing between these two mechanisms with the use of inducible animal models.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Figure 1:Accumulation of Syntaxin 3 in cone photoreceptors.Scale bar: 10 microns.
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