Johns Hopkins School of Medicine

The Role of Frizzled Receptors in Mammalian Development and Disease

The Nathans laboratory is focused on several broad and related areas of research: (1) neural and vascular development, and (2) the role of Frizzled receptors in mammalian development. We use gene manipulation in the mouse, cell culture models, and biochemical reconstitution to investigate the relevant molecular events underlying these processes, and to genetically mark and manipulate cells and tissues. Mammalian genomes have ten distinct Frizzled genes. The Frizzled proteins are cell surface receptors that are activated by members of the Wnt family of ligands, of which there are nineteen in mammals. In this system ligand-receptor relationships are complex, in that one type of Wnt can bind to different Frizzleds, and one type of Frizzled can bind to different Wnts. A completely unrelated ligand, Norrin, binds selectively to Frizzled4, a finding that suggests that other Frizzled receptors may also have non-Wnt ligands. Three distinct signaling pathways can be activated downstream of Frizzled receptors, and a large number of extracellular modulators of Frizzled signaling have been identified. Our mouse knockout studies have thus identified phenotypes for eight of the ten Frizzled receptors. Among the processes that are controlled by Frizzled receptors, either singly or in various combinations, are: axon guidance in the spinal cord and forebrain, hair follicle orientation on the body surface, neural tube closure, palate closure, closure of the ventricular septum, inner ear sensory hair cell orientation, production of capillaries in the retina, survival the vasculature in the inner ear, development of the blood brain barrier, survival of neurons in the parafascicular nucleus of the thalamus, closure of the ventral furrow in the eye, regression of the hyaloid vasculature, and growth of the kidney. Current experiments are aimed at defining additional Frizzled-regulated processes and elucidating the molecular mechanisms and cell biologic results of Frizzled signaling within these various contexts. Complementing these areas of biologic interest, we have ongoing technology development projects related to (1) genetically manipulating and visualizing defined cell populations in the mouse, and (2) quantitative analysis of mouse visual system function.