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| A false color image of a single cultured
growth cone indicates high relative concentrations of fibrillar
actin with warm colors. |
Developmental Neurobiology, Axon Guidance, Synapse Formation
Cell and tissue culture; Molecular biology; Protein biochemistry; Videomicroscopy, expression cloning; Zebrafish
We are studying how the growth cones of extending axons navigate through the developing embryo. Growth cones are guided by their responses to specific signaling molecules in their environment. These cues are generally divided into two general categories: those that promote outgrowth and those that inhibit outgrowth. A major emphasis of ours has been to develop in vitro assays that allow us to identify and characterize inhibitory cues.We were the first laboratory to identify a repellent axonal guidance cue, now named Semaphorin 3A. We are currently using an expression screen to identify additional novel axonal reppelents. In another line of inquiry we have identified G-protein coupled receptors whose activation reduces axonal responses to inhibitory cues. We think of the ligands that activate these receptors, for example the chemokine SDF1 and the neurotransmitter glutamate, as modulator signals. We are now examining interactions between repellents and modulators in the guidance of retinal and sensory axons in the embryonic zebrafish. In a related project we are also examining the role that these modulators of repellent function play in the formation of synapses. Our long term goal is to understand how repellent and modulatory cues control neuronal interconnections in the developing embryo and during the regeneration of damaged connections in the mature central nervous system.
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A retinal
growth cone loses its normal motile structure and is paralyzed
when it touches a sympathetic axon in culture. |
KEY WORDS: Development; growth cones; axon guidance; cell motility; regeneration, zebrafish.
Renzi, M.J. T.L.Wexler, and J.A. Raper (2000)
Olfactory sensory axons expressing a dominant negative semaphorin
receptor component enter the CNS early and overshoot their target.
Neuron,28:437-447. Source
Niclou, S.P., L.Jia, and J.A. Raper (2000) Slit2 is a repellent
for retinal ganglion cell axons. J Neurosci. 20:4962-74.
Source
Feiner,L, A.L.Webber, C.B.Brown, M.M.Lu, L.Jia, P.Feinstein, P.Mombaerts, J.Epstein, and J.A.Raper (2001) Targeted disruption of Semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128: 3061-3070. Source
Chalasani SH, Sabelko KA, Sunshine MJ, Littman DR, Raper JA. (2003)
A chemokine, SDF-1, reduces the effectiveness of multiple axonal
repellents and is required for normal axon pathfinding. J Neurosci.
23:1360-71. Source
Chalasani S.H., F. Baribaud, C.M. Coughlan, M.J. Sunshine, V.M.Y. Lee, R.W. Doms, D.R. Littman and J.A. Raper (2003) The chemokine SDF-1 promotes the survival of embryonic retinal ganglion cells. J. Neurosci. 23:4601-4612. Source
Kreibich TA, Chalasani SH, Raper JA. (2004) The neurotransmitter glutamate reduces axonal responsiveness to multiple repellents through the activation of metabotropic glutamate receptor 1. J Neurosci. 24(32):7085-95.
Source
