Inherited and acquired retinal vascular disorders are a leading cause of blindness in the United States. The laboratory of Dr. Jeremy Nathans at Johns Hopkins Medical School has defined and characterized one of the central signaling systems that regulates vascular development in the vertebrate retina?the activation of the endothelial cell receptor Frizzled4 (Fz4) and coreceptor Lrp5 by the paracrine action of the Muller glia-derived ligand Norrin?and described how perturbations in this pathway cause a series of inherited retinal vascular disorders in humans. Recent findings from our lab now indicate that Fz4 is a pan-endothelial receptor that continues to be expressed in the mature retinal blood vessels of adult mice, suggesting that Fz4 functions may be required for the maintenance of mature blood vessels or how they respond to ischemic retinopathy. Also, we have identified a transcription factor, Sox17, which appears to be a downstream effector of Norrin/Fz4 signaling in the developing retinal vasculature. This training fellowship consists of two aims, the first of which proposes to characterize the in vivo functions of Fz4 in mature retinal blood vessels using conditional Fz4 mice that permit the manipulation of Fz4 signaling only after the adult vascular plexus has fully developed. Using these mice, we will also investigate the functions of Fz4 in ischemic retinopathy by characterizing the pattern and time course of new blood vessel growth in response to laser-induced retinal artery and vein occlusion.
The second aim proposes to characterize the in vivo functions of Sox17 in retinal vascular development using conditionally targeted Sox17 mice that permit gene inactivation, via Cre-mediated recombination, specifically in endothelial cells. To help facilitate these studies, we are generating mouse lines that will enable us to fluorescently label the actin cytoskeleton and specific subpopulations of retinal endothelial cells. Together, these aims will provide important insight into the functions of the Norrin/Fz4 signaling pathway in vascular health, with the long term goals of developing innovative medical treatments for congenital and acquired retinal vascular disorders.
The Nathans laboratory has previously demonstrated that the Norrin/Frizzled-4 signaling pathway is essential for proper retinal angiogenesis in mice and humans. This proposal now seeks to characterize the functions of downstream transcriptional mediators using loss-of-function mouse mutants, while also investigating potential functions of Norrin/Frizzled-4 signaling in retinal neovascularization. The anticipated results will increase our mechanistic understanding of signaling molecules that have critical roles in the development and maintenance of retinal vasculature, perturbations to which are a leading cause of blindness.
|Tischfield, Max A; Robson, Caroline D; Gilette, Nicole M et al. (2017) Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura. Dev Cell 42:445-461.e5|