The process of motor axonal guidance and the ensuing process of neuromuscular synapse formation are spatially and temporally precisely coordinated, yet how this achieved at the molecular-cellular level is not well understood. One key player in this process is the vertebrate specific gene muscle specific kinase, MuSK, which aligns the path of incoming motor axon with the location of postsynaptic elements to the muscle center. We have compelling evidence that zebrafish unplugged/MuSK binds wnt11r to initiate this process through a dishevelled dependent signaling cascade, thereby restricting growth cones and synaptic prepattern to the muscle center through a mechanism reminiscent of planar cell polarity (PCP). A major implication is that the spatial alignment between presynaptic growth cones and postsynaptic development might be transmitted through a signaling pathway known to position cellular structures or processes at defined positions within the tissue plane. Specifically, unplugged/ MuSK might play a broader than previously anticipated role to organize a common central muscle zone to which pioneering growth cones and the first acetylcholine receptor clusters are restricted. The objective of the studies described here are threefold. (1) Determine the mechanism through which Wnt signals activate unplugged/MuSK function (through functional studies and live cell imaging to examine the cellular localization of unplugged/MuSK in response to Wnt signals). (2) Determine the extent of similarity between 'classical'PCP and unplugged/MuSK downstream signaling (through functional studies and live cell imaging). (3) Lastly, to maximize our understanding of motor axon guidance, it is critical to analyze and clone two newly identified genetic players in this process, turn out and rush hour (through cellular experiments and molecular cloning). These studies are directly relevant to the study of human disease, since genes known to direct axonal growth and synapse formation are implicated in the cause of human disease states and human inherited disorders, and might also play a role in regeneration after nerve injury.

Public Health Relevance

How motor axons navigate without errors over long distances and select their appropriate synaptic muscle targets, is not fully understood. Using genetic studies, live cell imaging and molecular biological studies, this proposal aims to understand how a key regulator gene, muscle specific kinase (MuSK), controls both axonal pathfinding and synapse formation. This is directly relevant to the study of child health and inherited disorders, because genetic defects in axonal pathfinding and synapse formation cause disorders such as horizontal gaze palsy with progressive scoliosis or congenital myasthenic syndrome.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037975-14
Application #
8440770
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Henken, Deborah B
Project Start
1999-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2013
Total Cost
$294,535
Indirect Cost
$105,494
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Sainath, Rajiv; Granato, Michael (2013) Plexin A3 and turnout regulate motor axonal branch morphogenesis in zebrafish. PLoS One 8:e54071
Banerjee, Santanu; Isaacman-Beck, Jesse; Schneider, Valerie A et al. (2013) A novel role for Lh3 dependent ECM modifications during neural crest cell migration in zebrafish. PLoS One 8:e54609
Lakhina, Vanisha; Marcaccio, Christina L; Shao, Xin et al. (2012) Netrin/DCC signaling guides olfactory sensory axons to their correct location in the olfactory bulb. J Neurosci 32:4440-56
Gordon, Laura R; Gribble, Katherine D; Syrett, Camille M et al. (2012) Initiation of synapse formation by Wnt-induced MuSK endocytosis. Development 139:1023-33
Rosenberg, Allison F; Wolman, Marc A; Franzini-Armstrong, Clara et al. (2012) In vivo nerve-macrophage interactions following peripheral nerve injury. J Neurosci 32:3898-909
Banerjee, Santanu; Gordon, Laura; Donn, Thomas M et al. (2011) A novel role for MuSK and non-canonical Wnt signaling during segmental neural crest cell migration. Development 138:3287-96
Burgess, Harold A; Schoch, Hannah; Granato, Michael (2010) Distinct retinal pathways drive spatial orientation behaviors in zebrafish navigation. Curr Biol 20:381-6

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