In the developing nervous system, neurons must extend axons to their correct targets to form an axon scaffold upon which functional neuronal connections are made. The migrating growth cone at the distal axon tip senses and responds to guidance information.
The aim of these studies is to use C. elegans to understand the cytoskeletal signaling networks that link axon guidance signals to changes in growth cone morphology and outgrowth via the actin cytoskeleton. In this proposal, genetic, molecular, and in vivo time-lapse growth cone imaging approaches will be used to dissect the roles of cytoskeletal signaling pathways in growth cone morphology and outgrowth. Many pathways and molecules have been identified that affect axon pathfinding. These experiments move beyond the "gene by gene" approach to studying axon pathfinding and instead are designed to understand how molecules relate to one another in pathways and networks to control axon pathfinding and growth cone morphology.
The first aim tests the idea that CDC-42 acts upstream of Rac GTPases in axon pathfinding.
The second aim focuses on the control of Rac GTPases by the TIAM-1/Still life Rac GTP exchange factor (GEF) downstream of CDC-42.
Aim 2 also is designed to test the role of the Cdc42 GEFs UIG-1/Clg and EXC-5/Fgd1 on regulation of CDC-42 in axon pathfinding.
The third aim i s to probe the role of the MIG-15 NIK kinase and RACK-1/Receptor for activated C kinase and their interaction with UNC- 115/abLIM downstream of CDC-42 in a Rac-independent pathway.
The fourth aim i ntegrates the first three and is to characterize the effects of these pathways on growth cone filopodia formation and morphology during outgrowth. The results of these experiments will significantly contribute to the goal of understanding the cytoskeletal signaling networks involved in growth cone morphology and will begin to address the cellular roles of these distinct pathways in axon development.

Public Health Relevance

Axon outgrowth is central to nervous system development and function. The goal of this proposal is to understand the basic molecular mechanisms of axon outgrowth, which will provide insight into the potential of axon regeneration after central nervous system injury and stroke as well as developmental mental retardation disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040945-11
Application #
8274690
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (02))
Program Officer
Riddle, Robert D
Project Start
2001-01-18
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2012
Total Cost
$307,544
Indirect Cost
$93,169
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Norris, Adam D; Sundararajan, Lakshmi; Morgan, Dyan E et al. (2014) The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP. Development 141:4395-405
Sundararajan, Lakshmi; Norris, Megan L; Schöneich, Sebastian et al. (2014) The fat-like cadherin CDH-4 acts cell-non-autonomously in anterior-posterior neuroblast migration. Dev Biol 392:141-52
Tamayo, Joel V; Gujar, Mahekta; Macdonald, Stuart J et al. (2013) Functional transcriptomic analysis of the role of MAB-5/Hox in Q neuroblast migration in Caenorhabditis elegans. BMC Genomics 14:304
Najarro, Elvis Huarcaya; Wong, Lianna; Zhen, Mei et al. (2012) Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development. J Neurosci 32:4196-211
Demarco, Rafael S; Lundquist, Erik A (2010) RACK-1 acts with Rac GTPase signaling and UNC-115/abLIM in Caenorhabditis elegans axon pathfinding and cell migration. PLoS Genet 6:e1001215
Lundquist, Erik A (2009) The finer points of filopodia. PLoS Biol 7:e1000142
Chapman, Jamie O; Li, Hua; Lundquist, Erik A (2008) The MIG-15 NIK kinase acts cell-autonomously in neuroblast polarization and migration in C. elegans. Dev Biol 324:245-57
Shakir, M Afaq; Jiang, Ke; Struckhoff, Eric C et al. (2008) The Arp2/3 activators WAVE and WASP have distinct genetic interactions with Rac GTPases in Caenorhabditis elegans axon guidance. Genetics 179:1957-71
Lundquist, Erik A (2006) Small GTPases. WormBook :1-18
Yang, Yieyie; Lu, Jiamiao; Rovnak, Joel et al. (2006) SWAN-1, a Caenorhabditis elegans WD repeat protein of the AN11 family, is a negative regulator of Rac GTPase function. Genetics 174:1917-32

Showing the most recent 10 out of 15 publications