Correct functioning of the visual system requires axonal connections from eye to brain to develop with precisely-defined spatial order. The broad long-term objective of our studies is to identify cell-cell signaling molecules, and characterize their functions and mechanisms of action in guiding the precise development of visual axonal connections. The proposal focuses on retinal ganglion cell axons, and their projections to the tectum, a retinal axon target which has long been a major model system.
Aim 1 proposes to study novel molecular interactions in the retinotectal system. The Amyloid Precursor Protein (APP) is a cell surface molecule with important roles in Alzheimer's pathology, but its normal functions are not well understood. APP has long been proposed to act as a cell surface ligand or receptor. In preliminary studies, binding partners for APP have been identified and are prominently expressed in the retinotectal system. Studies will be continued into the molecular interactions of these proteins, and their effects on APP signaling and retinal axon growth and development.
Aim 2 is to study mechanisms of tectal gradient formation. Ephrins are known to act as graded positional labels for axon mapping in the tectum. However, the mechanisms that initially set up these gradients are not well understood. Studies will be continued to identify the steps in the upstream molecular hierarchy that initially convert a non-graded to a graded distribution, and to identify biochemical mechanisms for gradient formation in the tectum.
Aim 3 is to characterize RNA-based mechanisms for regulation in retinal axons. Evidence has accumulated to show that regulated protein synthesis occurs within axons and can have important functions. This has opened up an exciting new field of study, but the mechanisms remain poorly characterized. RNA-based regulation mechanisms will be studied in retinal ganglion cell axons, including the location and dynamics of synthesis, and mechanisms for regulated translation of mRNAs in response to extracellular cues. While our primary goal is to elucidate basic molecular mechanisms, the work has broader implications for disease. APP is important for its roles in Alzheimer's disease, including pathology of the retina. Identification of ligands that regulate APP processing may lead to therapeutic targets to inhibit production of beta amyloid. More generally, studies to identify and characterize novel cell-cell signaling cues in the visual system, may lead to therapeutic agents for maintenance, repair or regeneration of visual connections.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011559-19
Application #
7922009
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (02))
Program Officer
Steinmetz, Michael A
Project Start
1996-09-30
Project End
2012-03-31
Budget Start
2010-09-30
Budget End
2012-03-31
Support Year
19
Fiscal Year
2010
Total Cost
$431,015
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Preitner, Nicolas; Quan, Jie; Li, Xinmin et al. (2016) IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories. Development 143:2753-9
Preitner, Nicolas; Quan, Jie; Nowakowski, Dan W et al. (2014) APC is an RNA-binding protein, and its interactome provides a link to neural development and microtubule assembly. Cell 158:368-382
Hancock, Melissa L; Preitner, Nicolas; Quan, Jie et al. (2014) MicroRNA-132 is enriched in developing axons, locally regulates Rasa1 mRNA, and promotes axon extension. J Neurosci 34:66-78
Preitner, Nicolas; Quan, Jie; Flanagan, John G (2013) This message will self-destruct: NMD regulates axon guidance. Cell 153:1185-7
Preitner, Nicolas; Flanagan, John G (2012) Axonal mRNA translation: an unexpected link to axon survival and the mitochondrion. Neuron 73:629-31
Coles, Charlotte H; Shen, Yingjie; Tenney, Alan P et al. (2011) Proteoglycan-specific molecular switch for RPTP? clustering and neuronal extension. Science 332:484-8
Tcherkezian, Joseph; Brittis, Perry A; Thomas, Franziska et al. (2010) Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141:632-44
Shen, Yingjie; Tenney, Alan P; Busch, Sarah A et al. (2009) PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326:592-6
Chen, Yao; Mohammadi, Moosa; Flanagan, John G (2009) Graded levels of FGF protein span the midbrain and can instruct graded induction and repression of neural mapping labels. Neuron 62:773-80
Osterfield, Miriam; Egelund, Rikke; Young, Lauren M et al. (2008) Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system. Development 135:1189-99

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