The central goal of the experiments in this proposal is to understand how neurons find their targets during development. It is now clear that this process involves the combined actions of attractive and repulsive guidance cues, both of which can act at short and long distances to steer neuronal growth cones. Recent work on members of the phylogenetically conserved semaphorin gene family, many of which can function in vivo and in vitro as repellents, suggests the exciting possibility that a thorough understanding of the cellular and molecular basis of semaphorin function will yield general principles of repulsive guidance mechanisms. Understanding how semaphorins affect the neuronal growth cone cytoskeleton will assist in understanding repulsive and inhibitory events that occur during adult life following neuronal injury or neuronal degeneration. In addition, since semaphorins function in immune system signaling events and have also been linked to the progression of certain types of cancers, the experiments we propose will have implications that extend far beyond how semaphorins mediate axon guidance during neural development. We have shown that the transmembrane semaphorin Sema 1a, like secreted semaphorins, functions in vivo to mediate repulsive guidance events. This work has resulted in the development of several genetic and molecular paradigms designed to identify the downstream signaling components used by Sema 1a to mediate repulsive neuronal guidance events. We have also begun an analysis of the function of certain vertebrate transmembrane semaphorins during neural development and have identified a novel protein (TSBP) that binds with high affinity to vertebrate thrombospondin domain-containing semaphorins and will aid in this endeavor. Accordingly, we propose to identify downstream signaling components that transduce repulsive neuronal guidance events mediated by Sema 1a in Drosophila using genetic and molecular strategies. We will also determine the role in vertebrate neural development played by thrombospondin domain-containing transmembrane semaphorins, using functional assays in defined embryonic neuronal populations and undertaking a detailed cellular and molecular analysis of TSBP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS035165-05S1
Application #
6319183
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Finkelstein, Robert
Project Start
1996-05-01
Project End
2005-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
5
Fiscal Year
2000
Total Cost
$45,000
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Jeong, Sangyun; Yang, Da-Som; Hong, Young Gi et al. (2017) Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila. Proc Natl Acad Sci U S A 114:E8254-E8263
Chak, Kayam; Kolodkin, Alex L (2014) Function of the Drosophila receptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance. Development 141:136-47
Riccomagno, Martin M; Sun, Lu O; Brady, Colleen M et al. (2014) Cas adaptor proteins organize the retinal ganglion cell layer downstream of integrin signaling. Neuron 81:779-86
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
Matsuoka, Ryota L; Sun, Lu O; Katayama, Kei-ichi et al. (2013) Sema6B, Sema6C, and Sema6D expression and function during mammalian retinal development. PLoS One 8:e63207
Cho, Joong Youn; Chak, Kayam; Andreone, Benjamin J et al. (2012) The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance. Genes Dev 26:2222-35
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
Wu, Zhuhao; Andreone, Benjamin J; Kolodkin, Alex L (2012) The coordinate regulation of sensory afferent CNS targeting and CNS longitudinal tract organization in Drosophila during neural development. J Peripher Nerv Syst 17 Suppl 3:34-7
Lloyd, Thomas E; Machamer, James; O'Hara, Kathleen et al. (2012) The p150(Glued) CAP-Gly domain regulates initiation of retrograde transport at synaptic termini. Neuron 74:344-60

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