Department of Molecular Biology & Genetics

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Jeremy Nathans - Professor Molecular Biology & Genetics 725 N. Wolfe Street 805A PCTB Baltimore, MD 21205 Office: 410-955-4679 Fax: 410-614-0827 jnathans@jhmi.edu

Assistant:	Theresa Stromsky

Molecular mechanisms of visual system development, function, and disease
Biology: Frizzled receptors in development and disease Our laboratory has focused for the past two decades on a large family of cell-surface receptors called Frizzled. This name refers to the appearance of fruit flies in which the receptor gene is mutated: the hairs and bristles on the body surface of Frizzled mutant flies are oriented inappropriately. In mammals, including humans, there are ten closely related Frizzled genes. In the mid-1990s, we showed, in collaboration with the laboratory of Roel Nusse at Stanford, that the principal ligands for Frizzleds are the Wnt proteins. There are 19 Wnt genes in mammals, and current evidence suggests that each Frizzled can bind to multiple of Wnts and each Wnt can bind to multiple Frizzleds. To add to the complexity, three distinct types of signals can be sent from Frizzled receptors to the cell interior. Our current focus is on defining the roles of Frizzled receptors in mammalian development. The foundation of our approach is the production and analysis of mice carrying targeted null or conditional null mutations in one or more Frizzled genes. We have constructed such lines for each of the ten Frizzleds, as well as for other genes that act in the same signaling pathways. This genetic analysis has revealed both diversity and unity in the functions of different Frizzled receptors, and has revealed the requirement for Frizzled signaling in a wide variety of developmental contexts, including axon guidance, vascular growth and differentiation, inner ear development, neural tube and palate closure, kidney development, and hair orientation on the body surface. In the context of vascular growth and differentiation, we identified a novel ligand (Norrin) that acts exclusively on the Frizzled (Frizzled4) that controls vascular development. In humans, mutations in the Norrin or Frizzled4 genes, or in genes coding for a co-receptor (Lrp5) or chaperone (Tspan12) produce vascular defects similar to their mouse counterparts. Current experiments are aimed at (1) identifying additional roles for Frizzleds in mammalian development, homeostasis, and disease, and (2) elucidating the molecular logic of Frizzled signaling. Technology: new tools for mouse genetics and neuroscience For the past decade we have been developing new genetic tools for visualizing and manipulating single identified cells in mice. Our approaches build on existing methods that use pharmacologic control of cre-loxP recombination. In one set of experiments we created a variety of knock-in alleles in which a pair of loxP sites flank the coding region and 3’ untranslated region (UTR) of a gene of interest, with a reporter gene inserted distal to the 3’-most loxP site. When the conditional knockout allele is placed over a WT allele, cre-mediated recombination creates heterozygous cells that exhibit reporter expression under the control of the promoter for the gene of interest. When the conditional knockout allele is placed over a conventional null allele in the gene of interest, cre-mediated recombination creates mutant cells that are similarly marked by expression of the reporter. By pharmacologic titration of cre activity, one can generate sparse mosaics of recombined cells, thereby permitting an analysis of individual mutant cells in an otherwise WT environment. Genetically-directed sparse recombination is especially useful for determining the morphology of genetically defined neurons. For some extremely large and complex neurons – such as forebrain cholinergic neurons, dopaminergic amacrine cells in the retina, and large cutaneous sensory neurons in the skin – visualizing the full structure of individual axonal or dendritic arbors has required labeling densities of only one or a few neurons per animal. Experiments currently in progress are extending these approaches to the visualization of distinct subcellular structures in individual identified cells and to the tracing of cell lineages in a variety of contexts.

Relevant Publications:	Yu, H., Ye, X., Guo, N. and Nathans, J. (2012) Frizzled2 and Frizzled7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes. Development 139: 4383-4394. PubMed Reference Wang, Y., Rattner, A., Zhou, Y., Williams, J., Smallwood, P.M., and Nathans, J. (2012) Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 151: 1332-1344. PubMed Reference Wu, H., Williams, J., and Nathans, J. (2012) Morphologic diversity of cutaneous sensory afferents revealed by genetically directed sparse labeling. eLife 1:e00181. PubMed Reference Badea, T.C., Williams, J., Smallwood, P., Shi, M., Motajo, O., and Nathans, J. (2012) Combinatorial expression of Brn3 transcription factors in somatosensory neurons: genetic and morphologic analysis. Journal of Neuroscience 32: 995-1007. PubMed Reference Ye, X., Wang, Y., Rattner, A., and Nathans, J. (2011) Genetic mosaic analysis reveals a major role for frizzled4 and frizzled8 in controlling ureteric growth in the developing kidney. Development 138: 11161-1172. PubMed Reference Cahill, H., Rattner, A., and Nathans, J. (2011) Preclinical assessment of central nervous system drug action using eye movements in mice. Journal of Clinical Investigation 121: 3528-3541. PubMed Reference Yu, H., Smallwood, P.M., Wang, Y., Vidaltamayo, R., Reed, R., and Nathans, J. (2010) Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes. Development 137:3707-3717. PubMed Reference Wang, Y., Chang, H., and Nathans, J. (2010) When whorls collide: the development of hair patterns in frizzled6 mutant mice. Development 137: 4091-4099. PubMed Reference 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. PubMed Reference Ye, X., Wang, Y., Cahill, H., Yu, Y., Badea, T.C., Smallwood, P.M., Peachey, N.S., and Nathans, J. (2009) Norrin, Frizzled4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 139: 285-298. PubMed Reference Badea, T.C., Hua, L.Z., Smallwood, P.M., Williams, J., Rotolo, T., Ye, X., and Nathans, J. (2009) New mouse lines for the analysis of neuronal morphology using CreER(T)/loxP-directed sparse labeling. Public Library of Science One 16: e7859. PubMed Reference Rattner, A., Toulabi, L., Williams, J., Yu, H., Nathans, J. (2008) The genomic response of the retinal pigment epithelium to light damage and retinal detachment. Journal of Neuroscience 28: 9880-9889. PubMed Reference 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. PubMed Reference Rotolo, T., Smallwood, P.M., Williams, J., and Nathans, J. (2008) Genetically-directed, cell type-specific sparse labeling for the analysis of neuronal morphology. Public Library of Science One 3: e4099. PubMed Reference 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. PubMed Reference 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. PubMed Reference 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. PubMed Reference 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. PubMed Reference 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. PubMed Reference

Graduate Program Affiliations	Biochemistry, Cellular & Molecular Biology (BCMB) Neuroscience Cellular and Molecular Medicine (CMM)