Our laboratory focuses on two broad areas of research: (1) retinal development and disease, (2) the role of Frizzled receptors in mammals. In the first of these areas, our general approach is to use the tools of molecular genetics to identify and manipulate genes involved in retinal development, function, and disease. The second area of interest focuses on all aspects of Frizzled function in mammals, which encompasses a wide variety of processes throughout development. These two areas of research have recently intersected with our discovery that one of the Frizzled receptors (Frizzled5) controls early events in eye development and a second Frizzled receptor (Frizzled4) controls the development of the retinal vasculature. The two areas are described in more detail below.

Much of our work on the retina is currently focused on (1) the development of retinal ganglion cells (RGCs), the output neurons that communicate directly to the brain, and (2) the response of the retina and retinal pigment epithelium (RPE) to injury and disease. The work on RGCs focuses on analyzing the contributions of various transcription factor genes by studying (in mice) targeted conditional mutations. Each mutation simultaneously alters an RGC’s genetic make-up and molecularly tags the cell so that its cell body, dendrites, and axon can be visualized. The work on the injury and disease response began with the identification of a set of genes that respond to a broad array of insults. Current efforts are directed at understanding the manner in which these genes are regulated and their roles in retinal homeostasis.

Mammalian genomes code for ten distinct Frizzled genes. The encoded Frizzled proteins are cell surface receptors that are activated by members of the Wnt family of ligands. The ligand-receptor relationship is complex in that one type of Wnt can bind to different Frizzleds, and one type of Frizzled can bind to different Wnts. Our studies on the control of retinal vascular development by Frizzled4 showed that a completely unrelated ligand, Norrin, binds selectively to Frizzled4, a finding that suggests that other Frizzled receptors may also have non-Wnt ligands. Our current emphasis is on defining the role of the Frizzleds in mammalian development by engineering mice in which one or more of the Frizzled genes have been either constitutively or conditionally deleted. In addition to the roles of Frizzled4 and Frizzled5 mentioned above, we have found that other Frizzled receptors control (either singly or in combination) neural tube closure, axon guidance, the orientation of sensory hair cells in the inner ear, and the patterning of hair follicles on the body surface. Current experiments are aimed at defining additional Frizzled-regulated processes and elucidating the molecular mechanisms of Frizzled signaling.

Complementing both of these areas of biologic interest, we have an ongoing program in technology development related to (1) mouse genetic manipulation and (2) quantitative analysis of mouse visual system function.

Publications:

Xu Q., Wang Y., Dabdoub A., Smallwood P.M., Williams J., Woods C., Kelley M.W., Jiang L., Tasman W., Zhang K., and Nathans J. (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 116: 883-895.
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Rattner, A., Chen, J., and Nathans, J. (2004) Proteolytic shedding of the extracellular domain of photoreceptor cadherin: implications for outer segment assembly. Journal of Biological Chemistry 279: 42202-42210.
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Chen, J., Rattner, A., and Nathans, J. (2005) The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes. Journal of Neuroscience. 25: 118-129.
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Rattner A., and Nathans J. (2005) The genomic response to retinal disease and injury: evidence for endothelin signaling from photoreceptors to glia. Journal of Neuroscience 25: 4540-4549.
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Wang Y., Zhang J., Mori S., and Nathans J. (2006) Axonal growth and guidance defects in Frizzled3 knockout mice: a comparison of diffusion tensor magnetic resonance imaging, neurofilament staining, and genetically directed cell labeling. Journal of Neuroscience. 26: 355-364.
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Wang Y., Guo N., and Nathans J. (2006) The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner ear sensory hair cells. Journal of Neuroscience. 26: 2147-2156.
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Wang, Y. Badea, T., and Nathans, J. (2006) Order from disorder: self-organization in mammalian hair patterning. Proceedings of the National Academy of Sciences USA 103: 19800-19805.
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Jacobs, G.H., Williams, G.A., Cahill, H., and Nathans, J. (2007) Emergence of novel color vision in mice engineered to express a human cone photopigment. Science 315: 1723-1725.
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Chen, J. and Nathans, J. (2007) Estrogen related receptor beta (NR3B2) controls epithelial cell fate and endolymph production by the stria vascularis. Developmental Cell 13: 325-337.
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Cahill, H. and Nathans, J. (2008) The optokinetic reflex as a tool for quantitative analyses of nervous system function in mice: application to genetic and drug-induced variation. Public Library of Science One 3: e2055.
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Rattner, A., and Nathans, J. (2008) The genomic response of the retinal pigment epithelium to light damage and retinal detachment. Journal of Neuroscience 28: 9880-9889.
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Liu, C., and Nathans, J. (2008) An essential role for Frizzled5 in mammalian ocular development: loss of Frizzled5 leads to microphthalmia, delayed closure of the optic fissure, persistence of the hyaloid vasculature, and a late retinal degeneration. Development 135: 3567-3576.
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Badea, T.C., Cahill, H., Ecker, J., Hattar, S., and Nathans, J. (2009) Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61: 852-864.