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 #
5R01NS040945-12
Application #
8471207
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
2013-06-01
Budget End
2014-05-31
Support Year
12
Fiscal Year
2013
Total Cost
$296,452
Indirect Cost
$89,580
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
Josephson, Matthew P; Chai, Yongping; Ou, Guangshuo et al. (2016) EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans. PLoS One 11:e0148658
Josephson, Matthew P; Miltner, Adam M; Lundquist, Erik A (2016) Nonautonomous Roles of MAB-5/Hox and the Secreted Basement Membrane Molecule SPON-1/F-Spondin in Caenorhabditis elegans Neuronal Migration. Genetics 203:1747-62
Sundararajan, Lakshmi; Norris, Megan L; Lundquist, Erik A (2015) SDN-1/Syndecan Acts in Parallel to the Transmembrane Molecule MIG-13 to Promote Anterior Neuroblast Migration. G3 (Bethesda) 5:1567-74
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
Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A (2013) Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans. Small GTPases 4:208-20
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
Alan, Jamie K; Lundquist, Erik A (2013) Mutationally activated Rho GTPases in cancer. Small GTPases 4:159-63
Demarco, Rafael S; Struckhoff, Eric C; Lundquist, Erik A (2012) The Rac GTP exchange factor TIAM-1 acts with CDC-42 and the guidance receptor UNC-40/DCC in neuronal protrusion and axon guidance. PLoS Genet 8:e1002665
Sundararajan, Lakshmi; Lundquist, Erik A (2012) Transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 control anterior-posterior neuroblast migration with left-right functional asymmetry in Caenorhabditis elegans. Genetics 192:1373-88

Showing the most recent 10 out of 25 publications