The fundamental organizing principle of axonal connections throughout the mammalian visual system, beginning with the projections of retinal ganglion cells (RGCs), is the arrangement of projections into retinotopic maps, organized to maintain the spatial arrangement of RGCs in the retina through the orderly terminations of their axons to the target, and thereby create a representation of the visual world in the brain critical for establishing high acuity vision. This proposal will address the molecular mechanisms that control the development of the retinotopic map within the projection of RGCs to the superior colliculus (SC), a primary target of RGCs, and the predominant model system for determining mechanisms that control the development of topographic maps in the visual system, as well as for other sensory systems. Our studies will use analyses ranging from determining the expression patterns and localization of the critical ligands, receptors and signaling molecules within RGC axons and the SC, biochemical studies to determine the receptor complexes formed by key guidance components and their influences on signaling pathways and function, use of in vitro axon guidance assays to determine the predominant function of guidance systems and receptor-ligand interactions, and in vivo analyses of the function and requirement of the guidance systems and their components using conditional knockout mice and complementary Cre lines to provide alternative and corroborative approaches. The proposed studies make use of approximately twenty lines of genetically engineered mice, and scores of compound lines. The proposal has 4 complementary Aims, each with multiple sub-Aims that test specific hypotheses suggested by our preliminary studies, previous findings, and computational modeling.
Aim 1 will demonstrate a novel functional relationship between the neurotrophin receptor TrkB and the EphA family of axon guidance receptors and that the complexing of EphA and TrkB enhances the repellent activity of EphA forward signaling required for retinotopic mapping in a BDNF independent manner.
Aim 2 will determine a role for BDNF - TrkB signaling in mediating the primary branching interstitially along RGC axons and branch arborization as a mechanism to complement the opposing gradients of repellent activities generated by EphA forward signaling and ephrin-A reverse signaling to generate topographic specificity in RGC axon branching and arborization.
Aim 3 will directly determine for the first time the involvement of ephrin-As as "receptors" for the repellent activity mediated by EphAs expressed in the SC, and will define novel co-receptors required to complex with the GPI-anchored ephrin-As to mediate their reverse signaling upon binding EphAs.
Aim 4 will test the prediction from computational modeling that ephrin- As present on RGC axons act as axon repellents that cooperate with ephrin-As endogenous to the SC to drive the large-scale remodeling of RGC axons through degenerative axon elimination required for the remodeling of the initially coarse retinocollicular map to establish a refined retinotopic map.

Public Health Relevance

The fundamental organizing principle of axonal connections throughout the mammalian visual system is the arrangement of projections into retinotopic maps for high acuity vision. This proposal addresses the molecular mechanisms that control retinotopic map development by the axons of retinal ganglion cells within the brain.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007025-28
Application #
8452699
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Steinmetz, Michael A
Project Start
1986-09-30
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
28
Fiscal Year
2013
Total Cost
$624,175
Indirect Cost
$296,524
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
McLaughlin, Todd; Lim, Yoo-Shick; Santiago, Alicia et al. (2014) Multiple EphB receptors mediate dorsal-ventral retinotopic mapping via similar bi-functional responses to ephrin-B1. Mol Cell Neurosci 63:24-30
Olsen, Olav; Kallop, Dara Y; McLaughlin, Todd et al. (2014) Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of ?-secretase. J Neurosci 34:6438-47
Feldheim, David A; O'Leary, Dennis D M (2010) Visual map development: bidirectional signaling, bifunctional guidance molecules, and competition. Cold Spring Harb Perspect Biol 2:a001768
Nikolaev, Anatoly; McLaughlin, Todd; O'Leary, Dennis D M et al. (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981-9
Lim, Yoo-Shick; McLaughlin, Todd; Sung, Tsung-Chang et al. (2008) p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59:746-58
Hoopfer, Eric D; McLaughlin, Todd; Watts, Ryan J et al. (2006) Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning. Neuron 50:883-95
McLaughlin, Todd; O'Leary, Dennis D M (2005) Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 28:327-55
O'Leary, Dennis D M; McLaughlin, Todd (2005) Mechanisms of retinotopic map development: Ephs, ephrins, and spontaneous correlated retinal activity. Prog Brain Res 147:43-65
Pak, Winnie; Hindges, Robert; Lim, Yoo-Shick et al. (2004) Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Cell 119:567-78
McLaughlin, Todd; Hindges, Robert; O'Leary, Dennis D M (2003) Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr Opin Neurobiol 13:57-69

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