. One of the great challenges in basic and clinical neuroscience is to understand fundamental organizing principles during nervous system wiring and to identify cell types and responses to molecular signals that sculpt the developing vertebrate brain. The goal of the proposed studies is to further explore molecular and cellular mechanisms of visual circuit formation, particularly those that influence postsynaptic neuronal morphology and connectivity during retinotectal wiring. Here, we will test the hypothesis that a subset of molecular signals interact to control dendritic arbor structure and connectivity in the intact, developing brain, where age-dependent responses influence both early growth and maintenance of a functional dendritic arbor. Over the years, the work of our laboratory has focused on the cellular and molecular mechanisms that control retinotectal circuit development by focusing on the role that the neurotrophic factor BDNF and the classical axon guidance molecules netrin-1, play during wiring events that follow successful retinal ganglion cell (RGC) axon pathfinding. The proposed studies build on the novel and important finding that netrin-1 plays a differential, but key role in the early development of neuronal morphology and connectivity of central neurons, particularly of those neurons that receive input from RGCs. Specifically, netrin influences the directionality of dendrite growth and the branching and pruning of optic tectal neuron dendritic arbors in a manner that is quite different from netrin regulation of RGC axon branching. In the proposed studies real-time imaging of neurons in developing Xenopus laevis embryos and state-of-the-art gain- and loss-of-function approaches will be used chronically and acutely manipulate netrin receptor signaling to demonstrate that regulated expression of netrin and its specific receptors shape postsynaptic connectivity in the retinotectal system by inducing both localized and rapid responses on developing dendrites of central neurons. These studies will also examine the hypothesis that developmental and activity related changes in netrin function impact visual circuit formation and the functional maturation of the visual circuit. Furthermore, our studies will establish that the cell adhesion molecule Down syndrome cell adhesion molecule (DSCAM) is required for dendrite self-avoidance and collaborates with netrin to establish the patterning of tectal neuron dendritic arbors. By imaging responses of genetically modified individual neurons in the intact, developing brain, our studies will advance our understanding of the early mechanisms that sculpt dendrites and synapses in the vertebrate brain, and further our knowledge of the organizing principles that shape functional connectivity in the central nervous system. Elucidating early molecular mechanisms of circuit development that differentially impact pre- and postsynaptic connectivity has broader implications for understanding human neurodevelopmental disorders in which altered brain function is associated with deficits in early connectivity, such as mental retardation and autism.

Public Health Relevance

One of the great challenges in basic and clinical neuroscience is to understand fundamental organizing principles during nervous system wiring and to identify responses by developing neurons to molecular signals that sculpt the developing brain. The proposed in vivo imaging studies will examine how two particular sets of molecules interact during development to guide the differentiation of neurons in the brain that directly receive visua information from the retina. By studying the early mechanisms that sculpt neurons and synapses in the vertebrate visual system we aim to provide valuable insights into fundamental mechanisms of synaptogenesis, and to advance the understanding of developmental deficiencies that can affect brain function.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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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
Marshak, Sonya; Meynard, Margarita M; De Vries, Ymkje A et al. (2012) Cell-autonomous alterations in dendritic arbor morphology and connectivity induced by overexpression of MeCP2 in Xenopus central neurons in vivo. PLoS One 7:e33153
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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