John Flanagan, Ph.D.

Professor of Cell Biology

Harvard Medical School
Cell Biology
240 Longwood Ave
Boston, MA 02115
Telephone: 617-432-4096
Fax: 617- 432-1144
Email: flanagan@hms.harvard.edu
Webpage: The Flanagan Lab Page
Predocs: 4 Postdocs: 6 Completed PhD's: 6

Our broad interest is to understand how cell-cell signaling molecules establish spatial pattern, particularly in the development of neural connections. Approaches include identification of novel signaling molecules, and functional analysis by molecular, cellular, genetic and embryological methods.

Identification of novel cell-cell signaling molecules. Using soluble receptor techniques developed in this lab, we identified some of the first members of a family of cell-cell signaling molecules, the ephrins, which have unique functions in neural development. We continue to develop and apply such techniques to identify other signaling molecules that should open up new areas of biology.

Wiring up the nervous system: cues for pathway selection and topographic mapping. During development, projecting axons first find their target regions by pathway selection. Then, within the target, axons typically form topographic maps, where the spatial arrangement of the projecting neurons is maintained in the order of their connections. We are interested in how the complex pattern of axonal pathways and maps is specified by extracellular guidance cues. Recent projects include dynamic regulation of pathfinding behavior in axons as they cross the spinal cord midline; and ephrins as graded labels specifying position in neural maps.

Molecular mechanisms for cellular interpretation of guidance information. We are also interested in intracellular signaling mechanisms, including downstream pathways that convert extracellular cues into an appropriately polarized cell response, and upstream mechanisms that regulate how axons respond to cues, including switches in responsiveness as growing axons reach intermediate and final targets. One class of mechanisms we are especially interested in currently are local protein translation and RNA-based control mechanisms within axons.

References:

• Lu, Q, Sun, EE, Klein, RS, and Flanagan, JG (2001) Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G-protein coupled chemoattraction. Cell 105:69-79.
• Brittis, PA, Lu, Q, and Flanagan, JG. (2002) Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110:223-235.
• Hansen, MJ, Dallal, GE, Flanagan, JG. (2004) Retinal axon response to A ephrins shows a graded, concentration-dependent transition from growth promotion to inhibition. Neuron 42:717-730.
• Johnson, KG, et al. (2006) The HSPGs Syndecan and Dallylike bind the receptor phosphatase LAR and exert distinct effects on synaptic development. Neuron 49:517-531.
• Flanagan, JG. (2006) Neural map specification by gradients. Curr. Op. Neurobiol. 16:59-66.