[Seminar] LRP2 mediates retinoid homeostasis to prevent myopia by Brian A. Link

[Seminar]

Title: LRP2 mediates retinoid homeostasis to prevent myopia

Speaker: Professor. Brian A. Link

Institution:

Department of Cell Biology, Neurobiology and Anatomy

Medical College of Wisconsin

Abstract:

Zebrafish with mutations in lrp2 result in pathological myopia.  Lrp2 is a large transmembrane protein involved in receptor-mediated endocytosis and trans-cellular trafficking.  Within the eye, Lrp2 protein is expressed exclusively in the retinal pigment epithelium and associated ciliary epithelia.  Lrp2 has many identified ligands, including the plasma retinol carrier, Rbp4.  Because altered retinoid signaling has been implicated in experimental myopia, we explored the role of this pathway in the lrp2 mutant phenotype.  Indeed, transcript analysis showed altered levels of retinoic acid (RA) target genes in lrp2 mutant eyes and serum retinol levels were significantly reduced compared to wild-type fish.  In addition, mutant fish exposed to RA-treated water from 1-2 months of age were more sensitive to its effects, including ocular enlargement, as compared to wild-type sibling controls. Furthermore, lrp2 mutants showed genetic interaction with mutants for modulators of retinoid homeostasis.  Finally, we constructed transgenic animals in which GFP-Rbp4 was secreted into the serum from liver hepatocytes, the endogenous source of Rbp4.  GFP-Rbp4 accumulated within the sclera and choroid layers of lrp2-/- mutant eyes, but not within those of wild-type sibling fish.  In vivo Florescent Recovery After Photobleaching (FRAP) analysis indicated that loss of Lrp2 prevented normal Rbp4-GFP uptake into RPE cells.  These and additional results suggest that Lrp2 associated with RPE cells controls homeostasis of periocular retinoids, and dysregulation of this process contributes to the observed high myopia in lrp2 mutant fish.

Biography:

The overarching research goal of the Link lab is to study the cellular basis of signaling and the role in development and relationships to disease processes. We primarily use zebrafish for our studies, combining imaging based technologies and genome editing.   In addition, we also use differentiated human induced pluripotent stem cells to complement the whole animal experiments. As part of this research we have developed tools to monitor and manipulate basic cellular processes such as endocytosis, vesicle trafficking and nuclear dynamics.  We have also created transgenic animals to investigate and quantitate signaling networks including Notch, BMP/Smad, and Hippo-Yap/Taz, as well as cellular stress pathways including the Unfolded Protein Response, Reductive-Oxidative Stress, and Autophagy.  There are several areas of research we are currently focused. A primary goal is to understand the cell biology and signaling events critical for ocular development and disease.  The biology of Lrp2 and Mfrp are two proteins currently under investigation.  Several of the signaling pathways are also important for cardiac development and regeneration, and we are pursuing research in that area as well. Additionally and integrated with our research goals, my lab emphasizes collaborative research and career-focused training for students and post-docs.