During neural development, axons extend through an environment containing a multitude of guidance molecules that influence their growth and direction. There is still relatively little known about how axonal growth cones are guided in the complex in vivo environment. We are interested in the particular axon guidance question of how two axon branches from one neuron are guided along separate pathways to distinct targets. Neurons often project axons to more than one target, and virtually nothing is known about how their axon branches are differentially guided. We use zebrafish spinal sensory neurons as a model because they are a simple neuronal type with well- characterized simple axon trajectories. These neurons extend two main axon branches, the central and peripheral axons, which display very different behaviors and trajectories. The goal of this project is to investigate mechanisms of guidance of these axons along their particular pathways and to elucidate the function of the molecular cues that guide them. The zebrafish embryo is an excellent system to investigate axon guidance mechanism in vivo because we can readily manipulate guidance molecules and image effects on dynamic behavior of axonal growth cones in the intact living embryo.
Our specific aims are 1) to use live imaging in vivo to characterize the behavior of the peripheral axon as it initially extends in an orthogonal direction to the central axon and exits the spinal cord, investigate the roles of two molecules known to be important for peripheral axon extension, and investigate the intracellular signaling events underlying the differential axon guidance;2) to identify and analyze the function of new molecules involved in sensory axon guidance;and 3) to characterize and clone the mutated gene from a mutant that has defective sensory axon pathways. Overall, our studies are designed to understand the processes involved in promoting and inhibiting axon growth, and patterning the complex arborization patterns of the nervous system. Knowledge of these mechanisms is important for understanding diseases of neural development and the conditions under which axon regeneration after injury can occur. Project Narrative: An understanding of the complex processes involved in promoting and inhibiting neuronal axon growth, and the functions of molecules that guide axons to their correct targets will be crucial for understanding diseases of neural development. Moreover, knowledge of these mechanisms will help to understand the conditions under which axon regeneration after injury can occur.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042228-07
Application #
7567495
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Riddle, Robert D
Project Start
2001-07-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
7
Fiscal Year
2009
Total Cost
$311,693
Indirect Cost
Name
University of Wisconsin Madison
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ponomareva, Olga Y; Eliceiri, Kevin W; Halloran, Mary C (2016) Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development. Neural Dev 11:2
Clay, Matthew R; Halloran, Mary C (2014) Cadherin 6 promotes neural crest cell detachment via F-actin regulation and influences active Rho distribution during epithelial-to-mesenchymal transition. Development 141:2506-15
Ponomareva, Olga Y; Holmen, Ian C; Sperry, Aiden J et al. (2014) Calsyntenin-1 regulates axon branching and endosomal trafficking during sensory neuron development in vivo. J Neurosci 34:9235-48
Clay, Matthew R; Halloran, Mary C (2013) Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition. Development 140:3198-209
Andersen, Erica F; Halloran, Mary C (2012) Centrosome movements in vivo correlate with specific neurite formation downstream of LIM homeodomain transcription factor activity. Development 139:3590-9
Andersen, Erica F; Asuri, Namrata S; Halloran, Mary C (2011) In vivo imaging of cell behaviors and F-actin reveals LIM-HD transcription factor regulation of peripheral versus central sensory axon development. Neural Dev 6:27
Clay, Matthew R; Halloran, Mary C (2011) Regulation of cell adhesions and motility during initiation of neural crest migration. Curr Opin Neurobiol 21:17-22
Clay, Matthew R; Halloran, Mary C (2010) Control of neural crest cell behavior and migration: Insights from live imaging. Cell Adh Migr 4:586-94
Andersen, Erica; Asuri, Namrata; Clay, Matthew et al. (2010) Live imaging of cell motility and actin cytoskeleton of individual neurons and neural crest cells in zebrafish embryos. J Vis Exp :
Sittaramane, Vinoth; Sawant, Anagha; Wolman, Marc A et al. (2009) The cell adhesion molecule Tag1, transmembrane protein Stbm/Vangl2, and Lamininalpha1 exhibit genetic interactions during migration of facial branchiomotor neurons in zebrafish. Dev Biol 325:363-73

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