Neurons in the retina make remarkably precise connections with their synaptic targets. Indeed, such precision is a hallmark of neuronal connectivity in many parts of the brain. These connections define the wiring diagram of the nervous system, and are critical to how the brain computes. Many of these connections are genetically programmed, forming in exactly the same pattern independent of visual experience, or the activity of the developing brain. However, the molecular mechanisms by which the genome encodes information about these connections, and the cell biological mechanisms by which these connections form during development are poorly understood. The visual system of Drosophila provides a unique context in which to use genetic, molecular genetic and histological techniques to define these mechanisms. The proposed experiments examine these mechanisms in the context of how specific cell adhesion and cell signaling molecules can guide axons to specific targets. How can precise connections be genetically hard-wired at the level of single cells and their processes? (Aim 1) How are differences in the relative levels of cell adhesion molecules translated into directed changes in axonal trajectory.
(Aim 2). How do cell signaling pathways specify which part of the visual system should be innervated? (Aim 3). How does the genetic machinery coordinate the choice of post-synaptic partner with the functional architecture of the retina? These experiments will define critical molecular mechanisms that underlie neural architecture. As mutations in the human homologs of the proteins studied here are associated with inherited forms of macular dystrophy and retinitis pigmentosa, understanding the normal functions of these molecules in mechanistic detail will inform novel therapeutic strategies in the treatment of eye disease.

Public Health Relevance

Mutations in a number of cellular proteins cause retinitis pigmentosa, retinal dystrophy and macular degeneration, causing impaired vision and blindness. This study will examine the functions of several of these proteins during eye development, will inform our broad understanding of how these proteins normally act, and will benefit the creation of new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015231-06
Application #
7654064
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Steinmetz, Michael A
Project Start
2009-09-30
Project End
2011-09-29
Budget Start
2009-09-30
Budget End
2010-09-29
Support Year
6
Fiscal Year
2009
Total Cost
$390,932
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Schwabe, Tina; Borycz, Jolanta A; Meinertzhagen, Ian A et al. (2014) Differential adhesion determines the organization of synaptic fascicles in the Drosophila visual system. Curr Biol 24:1304-1313
Schwabe, Tina; Neuert, Helen; Clandinin, Thomas R (2013) A network of cadherin-mediated interactions polarizes growth cones to determine targeting specificity. Cell 154:351-64
Hwa, Jennifer J; Clandinin, Thomas R (2012) Apical-basal polarity proteins are required cell-type specifically to direct photoreceptor morphogenesis. Curr Biol 22:2319-24
Schwabe, Tina; Clandinin, Thomas R (2012) Axon trapping: constructing the visual system one layer at a time. Neuron 75:6-8
Gontang, Allison C; Hwa, Jennifer J; Mast, Joshua D et al. (2011) The cytoskeletal regulator Genghis khan is required for columnar target specificity in the Drosophila visual system. Development 138:4899-909
Gohl, Daryl M; Silies, Marion A; Gao, Xiaojing J et al. (2011) A versatile in vivo system for directed dissection of gene expression patterns. Nat Methods 8:231-7
Prakash, Saurabh; McLendon, Helen M; Dubreuil, Catherine I et al. (2009) Complex interactions amongst N-cadherin, DLAR, and Liprin-alpha regulate Drosophila photoreceptor axon targeting. Dev Biol 336:10-9
Clandinin, Thomas R; Feldheim, David A (2009) Making a visual map: mechanisms and molecules. Curr Opin Neurobiol 19:174-80
Chen, Pei-Ling; Clandinin, Thomas R (2008) The cadherin Flamingo mediates level-dependent interactions that guide photoreceptor target choice in Drosophila. Neuron 58:26-33
Mast, Joshua D; Tomalty, Katharine M H; Vogel, Hannes et al. (2008) Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy. Development 135:2669-79

Showing the most recent 10 out of 15 publications