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Signaling Pathways That Control Development and Disease in the Mammalian Retina and Embryo
Summary: Jeremy Nathans uses molecular genetic approaches to study the development of the mammalian retina and embryo. The twin goals of this work are to understand the molecular and cellular mechanisms of pattern formation during development and the molecular and cellular basis of human disease.
Our laboratory is interested in the mammalian visual system and, in particular, the retina, the light-absorbing sheet of cells that lines the back of the eye. Our general approach is to use the tools of molecular genetics to identify and study genes involved in development, function, and disease. A second interest is in elucidating the mechanisms of pattern formation during animal development and, in particular, the role of the Frizzled family of cell-surface receptors. These two interests have converged with our discovery of a Frizzled-based system for controlling the development of retinal blood vessels.
Mammalian genomes encode 10 distinct Frizzled receptors. Fifteen years ago we showed, in collaboration with the laboratory of Roel Nusse (HHMI, Stanford University), that Frizzleds are the receptors for the Wnt family of ligands. However, the ligand-receptor relationships are complex: one type of Wnt can bind to different Frizzleds, and one type of Frizzled can bind to different Wnts. 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; Frizzled1 and Frizzled2 in the development of the heart and palate; and Frizzled4 in the development of the retinal vasculature.
Nini Guo, a graduate student, engineered a line of mice lacking Frizzled6 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 organized into large-scale patterns such as whorls. Research specialist Yanshu Wang and postdoctoral fellows Tudor Badea and Hao Chang have analyzed the developmental origin of these macroscopic patterns. They observe that the nearly perfect alignment of hairs on the body of a wild-type mouse is produced by a subtle reorientation of follicles that are initially not perfectly aligned, and that the Frizzled6 mutant hair patterns are produced by a substantial reorientation of follicles that initially appear to be randomly oriented or severely misoriented.
Despite their large size, both Frizzled6 mutant and wild-type hair follicles display a remarkable plasticity, reorienting 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 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. At present, the molecular and cellular mechanisms responsible for orienting hair follicles are largely unknown. We suspect that interactions between the individual elements in a variety of complex biological structures—such as cells within an epithelium or axons within a fiber tract—use some of the same "rules" that we have observed in the hair follicle system, even if the detailed molecular mechanisms differ, an idea that is supported by our work on Frizzled3 (described below). It is also 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 a population and to enhance precision in the context of imprecise individual responses.
Frizzled3 controls the directional growth of axons in the embryonic brain. 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 the highly homologous Frizzled3 and Frizzled6 receptors, Yanshu Wang and Nini Guo 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 common congenital defect in humans. The double-mutant mice also exhibit a defect in the orientation of sensory cells in the inner ear. We suspect that each of these developmental processes—neural tube closure, axonal pathfinding, 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 movements or orientations with the overall body plan.
Frizzled1 and Frizzled2 also act redundantly, but Huimin Yu, a graduate student, has shown that they are important in a different set of developmental processes: closure of the palate, the structure that forms the roof of the mouth, and closure of the ventricular septum, the wall that separates the left and right ventricles of the heart. Defects in these two closure processes are among the most common birth defects in humans. The observation that Frizzled signaling plays a central role in a variety of tissue closure processes suggests that these processes share a fundamental mechanistic similarity despite their diverse anatomic contexts.
The function of Frizzled4 is quite different from the functions of the Frizzleds described above. Loss of Frizzled4, in either mice or humans, results in a failure to fully develop a vascular system in the retina. Several years ago, Qiang Xu, a postdoctoral fellow, together with Yanshu Wang, discovered that Frizzled4 is the receptor for an unusual ligand, Norrin. Norrin is structurally unrelated to the Wnt proteins, which, as noted above, are the principal ligands for the Frizzled receptor family. In humans and mice, mutations in Norrin also cause hypovascularization of the retina, as do mutations in two Frizzled-associated membrane proteins, Lrp5 and Tspan12, that are part of the transmembrane signaling complex. Xin Ye, a graduate student, has shown that Norrin is produced by glial cells and Frizzled4 functions in vascular cells. This work defines a new signaling system that controls vascular development in the retina, and it unifies a set of previously unrelated disorders of human retinal vascular development.
As of May 30, 2012
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