Netrin-1 is a secreted molecule that can function as either an attractant or repellent during axon guidance. In the visual system, netrin has been implicated in the guidance of optic axons out of the eye towards their targets in the brain. Our long-term goal is to elucidate the regulatory mechanisms controlling the development of proper connections between the retina and its central targets. Here, we propose to test the hypothesis that netrin-1 is implicated in late aspects of retinotectal development that significantly impact visual function. Specifically, we aim to demonstrate that;1) netrin-1, through independent signaling on specific receptor subtypes, influences retinal axons at the target and their postsynaptic neurons in the brain, and 2) proper retinotectal wiring requires functional interactions between netrin and brain-derived neurotrophic factor (BDNF), a trophic factor that modulates synaptogenesis. We base these hypotheses on the observations that;i) netrin influences retinal axons past the period of retinal axon pathfinding, ii) the two netrin receptors deleted-in-colorectal cancer (DCC) and UNC-5 are expressed in complementary patterns during retinotectal development and, iii) BDNF and netrin share common signaling mechanisms to influence axon guidance. Real-time imaging experiments and spatially and temporally controlled manipulations in netrin signaling will be performed in living Xenopus tadpoles to examine netrin's role in visual system development. The specific hypotheses to be tested are: 1. Netrin-1, through DCC receptor activation, instructs retinal axons where to terminate and shapes optic axon arbor structure and synaptic connectivity. Manipulations in netrin levels and DCC signaling within the optic tectum will be used to analyze the role of netrin in axon targeting, branching, and presynaptic site differentiation. 2. Netrin-1, through UNC-5 receptor signaling, influences the morphological and synaptic development of postsynaptic tectal neurons. In vivo imaging experiments will be used to establish whether netrin participates in early dendritogenesis, controlling the orientation of pioneer dendritic processes and whether netrin modulates dendritic branching and postsynaptic site differentiation. 3. Netrin and BDNF interact functionally to shape retinotectal synaptic connectivity. Molecular and in vivo imaging studies will examine if netrin signaling through DCC receptors is upstream of BDNF regulation of retinal axon branching and synaptogenesis. The ability of BDNF to rescue retinal axons affected by altered DCC signaling will also be tested. Collectively, the proposed studies will reveal that netrin-1 is a key player in retinotectal circuit development and will further our understanding of the mechanisms that control the development of visual pathways, that are critically important in the maintenance of normal visual function.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Central Visual Processing Study Section (CVP)
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Steinmetz, Michael A
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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Igarashi, Miki; Santos, Rommel A; Cohen-Cory, Susana (2015) Impact of maternal n-3 polyunsaturated fatty acid deficiency on dendritic arbor morphology and connectivity of developing Xenopus laevis central neurons in vivo. J Neurosci 35:6079-92
Nagel, Anastasia N; Marshak, Sonya; Manitt, Colleen et al. (2015) Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo. Neural Dev 10:14
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Shirkey, Nicole J; Manitt, Colleen; Zuniga, Liliana et al. (2012) Dynamic responses of Xenopus retinal ganglion cell axon growth cones to netrin-1 as they innervate their in vivo target. Dev Neurobiol 72:628-48
Cohen-Cory, Susana; Kidane, Adhanet H; Shirkey, Nicole J et al. (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70:271-88
Nikolakopoulou, Angeliki Maria; Meynard, Margarita M; Marshak, Sonya et al. (2010) Synaptic maturation of the Xenopus retinotectal system: effects of brain-derived neurotrophic factor on synapse ultrastructure. J Comp Neurol 518:972-89
Manitt, Colleen; Nikolakopoulou, Angeliki M; Almario, David R et al. (2009) Netrin participates in the development of retinotectal synaptic connectivity by modulating axon arborization and synapse formation in the developing brain. J Neurosci 29:11065-77
Cohen-Cory, Susana (2008) Spatially patterned gradients of synaptic connectivity are established early in the developing retina. J Biol 7:15
Sanchez, Analiza L; Matthews, Benjamin J; Meynard, Margarita M et al. (2006) BDNF increases synapse density in dendrites of developing tectal neurons in vivo. Development 133:2477-86
Hu, Bing; Nikolakopoulou, Angeliki Maria; Cohen-Cory, Susana (2005) BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo. Development 132:4285-98

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