- Department of Ophthalmology
- Department of Biochemistry and Molecular Biophysics
- Professor of Ophthalmic Sciences (in Ophthalmology and in the Naomi Berrie Diabetes Center)
- Professor of Biochemistry and Molecular Biophysics
The nervous system is unique and remarkable in the complexity of the precise interconnections among its component cells. The human brain is composed of roughly ten billion neurons, each of which can participate in thousands of connections. Thus, the genetically-directed assembly of the nervous system involves formation of about 1013 specific interconnections between neurons. Implementation of this extraordinarily precise program depends on the controlled spatial and temporal expression of selective adhesion molecules on neural cell surfaces. Although the full complement of proteins responsible for specific adhesion in the nervous system remains unclear, many families of neural adhesion molecules have been identified and studied in detail. Our focus is on structural studies of neural adhesion molecules to reveal the molecular basis of their function and atomic-level details of their binding specificity.
Much of our efforts are focused on the cadherins, a large family of cell surface proteins that mediate adhesive binding between cells in both vertebrates and invertebrates. Crystal Structures of cadherins show that binding interactions form only between the N-terminal domains of the extracellular regions. The idea that these domains encode cadherin cell adhesive specificity has been verified by structre-based mutagenesis experiments. There are several subfamilies of cadherins expressed in the nervous system, including type I, type II, and protocadherins. The sorting of motor neuron pools is dependent on the unique distributions of type II cadherins expressed by the cells of each motor neuron pool.
Our long-term goal is to determine the atomic-level basis for specific adhesion in a variety of neural systems.
The lab focuses mainly on the biology of cell adhesion, particularly as it relates to
establishing synaptic connections between neurons, using the retina as the primary
model system. Research in the lab encompasses both molecular-level studies using
X-ray crystallography to understand the structure and function of individual proteins, as well as cellular and histologic studies to understand their roles in vivo.
There are two primary projects underway in our laboratory: (1) We are examining the
structure, function, and retinal expression of a family of putative neural cell adhesion
proteins called protocadherins. These proteins, which are distinct from yet resemble
cadherin cell adhesion proteins, are expressed with a remarkable specificity: Neurons of identical lineage in close proximity to each other appear to choose one or a few protocadherins to express (of the 52 in the genome), and this choice differs from one cell to the next. Protocadherins are localized primarily at synapses, suggesting the possibility that their differential adhesion may be important in wiring neural circuits. To investigate this possibility, we have produced specific antibodies to 15 of the 52 protocadherins, and using immunohistochemistry are in the process of correlating the expression of these proteins with the known neural circuits of the retina. (2) We are also investigating the biology of tubby proteins, which we have shown to function as signaling factors downstream from heterotrimeric G-proteins. The tubby mutant mouse exhibits an obesity/insulin-resistance/retinopathy phenotype, and dysfunction of tubby-like protein 1(TULP1) is the cause of retinitis pigmentosa type 14. A collaborator in France has identified a human tubby mutants who exhibit a syndrome similar to that of the tubby mouse. We are now working to understand the biochemical origin of the dysfunction of these mutants.
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- Chen, C.P., Posy,S., Ben-Shaul, A., Shapiro, L., Honig, B. (2005).Specificity ofcell-cell adhesion by classical cadherins: critical roleforlow-affinity dimerization through beta-strand swapping. PNAS, 102:8531-6
- Patel,S.D., Chen, C.P., Bahna, F., Honig, B., and Shapiro, L.(2003).Cadherin-mediated cell-cell adhesion: sticking together as afamily.Curr. Opin Struct. Biol., 13: 690-698.
- Boggon, T.J., Murray, J., Chapuis-Flament, S., and Shapiro, L.(2002).Crystal Structure of the C-cadherin Ectodomain and Implicationsfor theMechanism of Adhesion. Science, 296: 1308-1313.