Harald JungeAssistant Professor
Porter room B359B
Explore Harald Junge's areas of research and more in Vivo
Molecular mechanisms of vascular development; vascular diseases of the retina; neurovascular interactions; Wnt signaling.
Blood vessels mediate a wide range of essential biological functions, e.g., in transport and physiological integration, induction of developmental programs, and maintenance of stem cell niches. Furthermore, the progression of prevalent human diseases - for instance vascular diseases of the retina - depends on processes of neovascularization. Our laboratory integrates molecular and protein-biochemical methods, cell biology, mouse genetics, and histological analysis to understand the signaling pathways that mediate vascular development. These efforts help us to understand how normal vascular biology is altered in vascular diseases, in particular retinal vascular diseases.
Pathways currently under study include Norrin-induced FZD4 signaling (Norrin/Frizzled4 signaling) in the retina. Norrin is a high affinity ligand for Frizzled4 and induces stabilization of beta-catenin and LEF/TCF-dependent gene transactivation. Initiation of Norrin/Frizzled4 signaling requires the co-receptor LRP5 and the ligand-specific co-activator TSPAN12 (a membrane protein of the tetraspanin family). Norrin/Frizzled4 signaling in endothelial cells is required for intraretinal angiogenesis and blood-retina barrier formation. Similarly, canonical Wnt/Frizzled signaling in the developing brain and spinal cord mediates CNS angiogenesis and blood-brain barrier formation. Dysfunction of Norrin/Frizzled4 signaling impairs or abolishes vision (e.g., in Norrie disease or familial exudative vitreoretinopathy aka FEVR).
In the past, our laboratory has focussed on the following questions:
Wnt/Frizzled interactions are in part promiscuous. Are there accessory receptor complex components that sharpen ligand-selectivity? TSPAN12 enhances specifically Norrin-induced Frizzled4 signaling in cell-based assays and is a component of the Norrin receptor complex. We found that TSPAN12 interacts with both Norrin and Frizzled4 and stabilizes their interaction. Tspan12 mutant mice display retinal vascular phenotypes that are also observed when Ndp (Norrin), Fzd4, or Lrp5 genes are disrupted. Together, these data establish TSPAN12 as an accessory receptor complex component that enhances ligand-selective responses. Mutations in the human TSPAN12 gene are linked to familial exudative vitreoretinopathy. We found that several FEVR-linked mutations impair trafficking of TSPAN12 to the cell surface and largely prevent the integration of TSPAN12 into the Norrin receptor complex.
Endocytosis of Wnt receptor complex components has been studied for regulatory roles in signaling, however, whether the canonical ligand Norrin induces endocytosis of its receptor complex remained unknown. We showed that Norrin is a potent trigger of FZD4 endocytosis and studied the functional role of this process in signaling, angiogenesis, and blood-CNS barrier formation. We introduced an inducible dominant negative VPS4b EQ mouse allele (R26 lox-STOP-lox VPS4b EQ) that can be used to study the multivesicular body pathway and other VPS4-dependent functions in vivo.
We explored how loss of Very low-density lipoprotein receptor (VLDLR) leads to severe pathological retinal neovascularization. Vldlr-/- mice are a model for retinal angiomatous proliferation, and the mechanism underlying this type of neovascularization is poorly understood. In a detailed phenotypic analysis, we showed that neovascularization occurs in the context of preceding developmental defects, including altered intraretinal capillary development and neurite mistargeting. Intriguingly, neovascular lesions develop in close association with mistargeted neurites, however, mistargeted neurites (at least those of horizontal cell neurons) are not necessary for the process of neovascularization (using Foxn4-/-;Vldlr-/- mice, which lack horizontal cells).
Ligand-Selective Wnt Receptor Complexes in CNS Blood Vessels: RECK and GPR124 Plugged In.
Neuron. 2017 Aug 30;95(5):983-985.
TSPAN12 is a Norrin Co-Receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling.
Lai MB, Zhang C, Shi J, Johnson V, Khandan L, McVey J, Klymkowsky MW, Chen Z, Junge HJ.
Cell Rep. 2017 Jun 27;19(13):2809-2822.
Norrin-induced Frizzled4 endocytosis and endo-lysosomal trafficking control retinal angiogenesis and barrier function.
Zhang C, Lai MB, Khandan L, Lee LA, Chen Z, Junge HJ.
Nat Commun. 2017 Jul 4;8:16050. doi: 10.1038/ncomms16050.
Neurite Mistargeting and Inverse Order of Intraretinal Vascular Plexus Formation Precede Subretinal Vascularization in Vldlr Mutant Mice.
Johnson V, Xiang M, Chen Z, Junge HJ.
PLoS One. 2015 Jul 15;10(7):e0132013.
TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling.
Junge, HJ, Yang, S, Burton, JB, Paes, K, Shu, X, French, DM, Costa, M, Rice, DS, and Ye, W.
Cell, 139(2):299-311. 2009
Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity.
Junge, HJ, Rhee, J, Jahn, O, Varoqueaux, F, Spiess, J, Waxham, MN, Rosenmund, C, and Brose, N.
Cell, 118(3):389-401. 2004