The central goal of the experiments in this proposal is to understand how neurons find their targets during neural development. Our current understanding of how various guidance cues and their receptors influence the establishment and maintenance of neuronal trajectories provides a platform upon which a thorough understanding of the signaling cascades which govern neuronal guidance can be built. The semaphorin family of phylogenetically conserved proteins contains many well characterized repulsive guidance cues. However, some semaphorins can act as attractants, and certain individual semaphorins have the capacity to act as both a repellent and an attractant. Therefore, defining the semaphorin signaling cascade will contribute to our understanding of how repulsive guidance is signaled to neuronal processes and also how this signaling is modulated. In addition to aiding our understanding of how growth cones navigate through complex extracellular environments during neural development, elucidation of semaphorin signaling cascades has important clinical implications. Semaphorin signaling has been linked to inhibition of neuronal extension following injury, to the progression of certain cancers, and to immune system function. Therefore, work proposed here has potential implications that extend beyond understanding how neuronal connectivity is established and maintained. We propose here to investigate how key semaphorin signaling cascade components steer neuronal processes. We have previously characterized two phylogenetically conserved different protein families, the MICALs and nervy/MTG proteins, each of which includes cytosolic proteins that play critical, but distinct, roles in promoting and modulating semaphorin-mediated repulsion in vivo. This work provides new insights for our current understanding of semaphorin signaling which can be applied to both invertebrate and vertebrate guidance events. Therefore, using approaches in both Drosophila and in rodents, we will address how these and other semaphorin signaling cascade intermediates ultimately facilitate the establishment and maintenance of neuronal connectivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS035165-16
Application #
8013518
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
1996-05-01
Project End
2012-09-29
Budget Start
2011-01-01
Budget End
2012-09-29
Support Year
16
Fiscal Year
2011
Total Cost
$438,405
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chak, Kayam; Kolodkin, Alex L (2014) Function of the Drosophila receptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance. Development 141:136-47
Koropouli, Eleftheria; Kolodkin, Alex L (2014) Semaphorins and the dynamic regulation of synapse assembly, refinement, and function. Curr Opin Neurobiol 27:1-7
Bharadwaj, Rajnish; Roy, Madhuparna; Ohyama, Tomoko et al. (2013) Cbl-associated protein regulates assembly and function of two tension-sensing structures in Drosophila. Development 140:627-38
Sun, Lu O; Jiang, Zheng; Rivlin-Etzion, Michal et al. (2013) On and off retinal circuit assembly by divergent molecular mechanisms. Science 342:1241974
Jeong, Sangyun; Juhaszova, Katarina; Kolodkin, Alex L (2012) The Control of semaphorin-1a-mediated reverse signaling by opposing pebble and RhoGAPp190 functions in drosophila. Neuron 76:721-34
Matsuoka, Ryota L; Nguyen-Ba-Charvet, Kim T; Parray, Aijaz et al. (2011) Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. Nature 470:259-63
Matsuoka, Ryota L; Chivatakarn, Onanong; Badea, Tudor C et al. (2011) Class 5 transmembrane semaphorins control selective Mammalian retinal lamination and function. Neuron 71:460-73
Huang, Zhiyu; Yazdani, Umar; Thompson-Peer, Katherine L et al. (2007) Crk-associated substrate (Cas) signaling protein functions with integrins to specify axon guidance during development. Development 134:2337-47
Ayoob, Joseph C; Terman, Jonathan R; Kolodkin, Alex L (2006) Drosophila Plexin B is a Sema-2a receptor required for axon guidance. Development 133:2125-35
Kantor, David B; Chivatakarn, Onanong; Peer, Katherine L et al. (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961-75

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