Wnt family proteins play important roles in axon pathfinding and target selection during the wiring of the nervous system. They provide directional information for the navigating growth cones and either attract or repel axons by signaling through specific receptors and signaling ways. Atypical PKC (aPKC), a key component of apical-basal (A-B) polarity signaling in neural epithelial cells, mediates Wnt attraction and anterior-directed turning of spinal cord commissural axons after midline crossing, a model system for axon guidance studies. Preliminary results showed that core Wnt/planar-cellpolarity (Wnt/PCP) signaling components are also required for A-P guidance of commissural axons. The renewal proposal will investigate whether the two epithelial polarity-signaling pathways are involved in mediating Wnt signaling in A-P axon guidance and, if so, how the two pathways are integrated. The cellular mechanisms of growth cone guidance, particularly membrane trafficking and its relationship with microtubule dynamics, are currently understudied. This proposal will tackle the role of membrane trafficking and microtubule dynamics in growth cone guidance. In addition, the role of Wnt signaling in brain wiring and formation of functional circuits are still poorly known. This proposal will use the brainstem monoaminergic axons as an inroad to study how Wnts organize distinct brain circuits to control behavior.
Aim 1 : Characterization of PCP and aPKC/A-B polarity signaling components in Wnt signaling and A-P axon guidance.
Aim 2 : Cellular mechanisms of PCP and PKCz/A-B polarity signaling pathways in growth cone guidance.
Aim 3 : Role of Wnt signaling in brain circuit wiring. Wnts are large family of proteins (19 members) with three diverse classes of receptors, the Frizzleds (10 members), Ryk and ROR2, all widely expressed in the nervous system. The Wnt guidance system likely plays major roles in wiring. The Wnt guidance system is re-induced after injury in adult spinal cord and regulates adult corticospinal tract axon regeneration. The proposed studies will enhance the understanding of the molecular and cellular mechanisms of CNS axon wiring in development as well as provide tools for nervous system regeneration following traumatic injury and degeneration of the CNS.

Public Health Relevance

The Wnt guidance system plays important roles in central nervous system wiring and is re-induced after injury in adult spinal cord and regulates adult corticospinal tract axon regeneration. The proposed studies will enhance the understanding of the molecular and cellular mechanisms of CNS axon wiring in development as well as provide tools for nervous system regeneration following traumatic injury and degeneration of the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047484-10
Application #
8432486
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2003-12-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$305,152
Indirect Cost
$98,280
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Onishi, Keisuke; Hollis, Edmund; Zou, Yimin (2014) Axon guidance and injury-lessons from Wnts and Wnt signaling. Curr Opin Neurobiol 27:232-40
Shafer, Beth; Onishi, Keisuke; Lo, Charles et al. (2011) Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1-mediated feedback inhibition in growth cone guidance. Dev Cell 20:177-91
Zou, Yimin (2011) When it is hard to get to with genetics--planar cell polarity under a chemical scalpel. Chem Biol 18:1350-1
Fenstermaker, Ali G; Prasad, Asheeta A; Bechara, Ahmad et al. (2010) Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem. J Neurosci 30:16053-64
Wolf, Alex M; Lyuksyutova, Anna I; Fenstermaker, Ali G et al. (2008) Phosphatidylinositol-3-kinase-atypical protein kinase C signaling is required for Wnt attraction and anterior-posterior axon guidance. J Neurosci 28:3456-67
Liu, Yaobo; Wang, Xiaofei; Lu, Chin-Chun et al. (2008) Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J Neurosci 28:8376-82