The long-term goal of this work is to identify the genetic mechanisms underpinning the development and function of the visual system in a systematic and unbiased fashion. In the period preceding this grant proposal, we have carried out forward-genetic screens in search of mutations that disrupt visual functions of zebrafish. We introduced new mutations at random positions in the genome using the chemical mutagen ethylnitrosourea. Semi-automated behavioral screening assays were devised and employed to detect deficits in visual processing in over 2,000 mutagenized families. We also screened over 400 existing zebrafish mutants. This effort led to the identification of over 80 mutants. In this grant, we will now study the orderly formation of retinotectal synapses using two of the mutants discovered in our screen. We are particularly interested in the role of axon-axon interactions and activity-dependent synaptic competition in determining the exact position and territory that an individual retinal arbor is occupying in the tectum. One of our mutants lacks all retinal ganglion cells -- its tectum is genetically depleted of visual input. We will now transplant single or few wildtype ganglion cells into this mutant and ask if the position and shape of the axon arbor is altered when no other retinal axons are present. Another mutant has altered synaptic transmission properties allowing us to ask what role electrical activity plays in shaping retinotectal connections and how an activity-deficient axon arbor develops when it is surrounded by axons with normal activity levels. Finally, we propose to generate transgenic lines that allow us to conditionally block synaptic transmission from ganglion cells to neurons in the tectum. Transplantations and single-axon labelings will again serve to reveal the role of activity and synaptic competition in the establishment and stabilization of neuronal connections. Health-relatedness. Human and fish visual systems are very similar. Our approach, therefore, may lead a way to understanding the molecular basis of inherited and acquired afflictions of the visual pathway in human patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012406-07
Application #
7099509
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Oberdorfer, Michael
Project Start
1999-02-15
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$361,669
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Thiele, Tod R; Donovan, Joseph C; Baier, Herwig (2014) Descending control of swim posture by a midbrain nucleus in zebrafish. Neuron 83:679-91
Jia, Sujuan; Muto, Akira; Orisme, Wilda et al. (2014) Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation. Hum Mol Genet 23:2981-94
Semmelhack, Julia L; Donovan, Joseph C; Thiele, Tod R et al. (2014) A dedicated visual pathway for prey detection in larval zebrafish. Elife 3:
Muto, Akira; Taylor, Michael R; Suzawa, Miyuki et al. (2013) Glucocorticoid receptor activity regulates light adaptation in the zebrafish retina. Front Neural Circuits 7:145
Robles, Estuardo; Filosa, Alessandro; Baier, Herwig (2013) Precise lamination of retinal axons generates multiple parallel input pathways in the tectum. J Neurosci 33:5027-39
Ziv, L; Muto, A; Schoonheim, P J et al. (2013) An affective disorder in zebrafish with mutation of the glucocorticoid receptor. Mol Psychiatry 18:681-91
Nevin, Linda M; Xiao, Tong; Staub, Wendy et al. (2011) Topoisomerase IIbeta is required for lamina-specific targeting of retinal ganglion cell axons and dendrites. Development 138:2457-65
Xiao, Tong; Staub, Wendy; Robles, Estuardo et al. (2011) Assembly of lamina-specific neuronal connections by slit bound to type IV collagen. Cell 146:164-76
Schoonheim, Peter J; Arrenberg, Aristides B; Del Bene, Filippo et al. (2010) Optogenetic localization and genetic perturbation of saccade-generating neurons in zebrafish. J Neurosci 30:7111-20
Del Bene, Filippo; Wyart, Claire; Robles, Estuardo et al. (2010) Filtering of visual information in the tectum by an identified neural circuit. Science 330:669-73

Showing the most recent 10 out of 25 publications