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Molecular Biology of Human Vision and of Developmental Patterning
Summary: Jeremy Nathans uses molecular genetic approaches to study the physiology and development of the retina and to understand the mechanisms of human retinal diseases. He is also investigating the molecular mechanisms of complex pattern formation during animal development.
Our laboratory is interested in the physiology and pathophysiology of the mammalian visual system, and in particular the retina, the light-absorbing sheet of cells that lines the back of the eye. The general approach is to use the tools of molecular genetics to identify and study genes involved in retinal development, function, and disease. A second interest is in elucidating the mechanism of complex pattern formation during animal development and, in particular, the role in this process of the Frizzled family of cell-surface receptors. Several years ago, these two interests intersected with our discovery of a Frizzled-based system for controlling the development of the retinal vasculature (blood vessels).
Mammalian genomes code for 10 distinct Frizzled genes. Ten years ago we showed, in collaboration with the laboratory of Roel Nusse (HHMI, Stanford University), that Frizzleds are cell-surface receptors that are activated by members of the Wnt family of ligands. The ligand-receptor relationship is complex: one type of Wnt can bind to different Frizzleds, and one type of Frizzled can bind to different Wnts. Moreover, our studies on the control of retinal vascular development by Frizzled4 showed that a completely unrelated ligand, Norrin, binds selectively to Frizzled4, which 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 deleted. This summary focuses on experiments that reveal the role of Frizzled3 and Frizzled6 in the development of the brain, inner ear, and skin.
Nini Guo, a graduate student, engineered a line of mice lacking Frizzled6 function and found that the mice exhibit unusual hair patterns. Frizzled6 is expressed in hair follicles and in the skin. In its absence, these structures look microscopically normal, but instead of the normal pattern of parallel hairs, the hairs over much of the body surface are either organized into large whorls or come together to form ridges. Yanshu Wang, a research specialist, and Tudor Badea, a postdoctoral fellow, have analyzed the developmental origin of these macroscopic patterns. They observe that the nearly parallel arrangement of hairs on the body of a wild-type mouse arises from fields of imperfectly aligned follicles and that the Frizzled6 mutant hair patterns arise from fields of grossly misoriented or randomly oriented follicles. Despite their large size, both mutant and wild-type hair follicles display a remarkable and unexpected plasticity, reorienting on a timescale of days in what appears to be a self-organized refinement process. The essential features of this process can be studied with a simple cellular automata model in which a local consensus "rule" acts iteratively to bias each hair's orientation in favor of the average orientation of its neighbors. These experiments define two systems for hair orientation: a global orienting system that acts early in development and is dependent on Frizzled6, and a local self-organizing system that acts later and is independent of Frizzled6.
Complex hair patterns are prevalent in a variety of mammals, including humans. In many species, including our own, individual variations in hair patterning are well documented. In classic work carried out in the 1930s and 1940s, the geneticist Sewall Wright demonstrated the inheritance of hair pattern variations in guinea pigs. Current evidence suggests that genetic factors may also be relevant in determining the patterning of hair whorls on the human scalp. The Frizzled6 work suggests that natural variation in these patterns may arise from sequence variation in the genes encoding Frizzled6 or other components that act in the same pathway. Finally, it is interesting that local consensus interactions, conceptually similar to those that align hair follicles, influence group behavior in a variety of complex social systems, including locust migration and fish schooling. These interactions presumably represent an economical way to propagate global signals across the population and to enhance precision in the context of imprecise individual responses.
Another Frizzled family member, Frizzled3, controls the development of axons within the brain. Several years ago, we showed that in the absence of this gene, many developing axons in the embryonic brain fail to navigate to their correct destinations. Although hair patterning and axonal navigation may seem like unrelated processes, both require that local structures (hairs or axons) sense the larger environment around them. To examine possible links between these processes, we generated mice that are missing both the Frizzled3 and Frizzled6 genes. These mice exhibit additional defects not seen with either single mutant. In particular, they fail to close the neural tube, a severe defect that also occurs in a variety of human disorders. The double-mutant mice also exhibit a defect in the orientation of sensory cells in the inner ear, which indicates that Frizzled3 and Frizzled6 act redundantly in the process of correctly orienting these cells. We suspect that all of these developmental processes—neural tube closure, axonal growth and navigation, hair patterning, and orienting inner ear sensory cells—utilize the same basic molecular machinery to read out the spatial coordinates of the tissues in which they operate. This system appears to be the body's equivalent of the global positioning system—a system that provides positional information to cells that must coordinate their movement or orientation with the overall body plan.
Last updated: July 31, 2007
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