The cellular architecture and connectivity of the vertebrate retina is remarkably conserved across species. What distinguishes these retinas most is the relative numbers of each of the different cell types. Even within a species, there is significant variation in the size of neuronal populations. Polymorphic genes controlling the processes regulating cellular production, fate assignment and survival contribute most of this variation between individuals, and the present investigation will seek to identify genes responsible for this variation, and to understand their role in those processes modulating proliferation, fate determination and apoptosis. Twenty-six recombinant inbred strains of mice derived from the A/J and C57BL/6J strains of mice will be used to determine the natural variation in four different types of retinal bipolar cell, and the degree of co-variation between cell types will be examined. The variation in bipolar cell number will also be compared with data for cone photoreceptor number and with new data collected for rod photoreceptors. Variation in cell number will be mapped to genomic loci where candidate polymorphic genes will be identified and tested using gene knock-out strategies. The role of cell death in establishing bipolar cell numbers, and its temporal occurrence, will be assessed directly in Bax knock-out mice, while its afferent-dependency will be defined in coneless and conefull mutant mice. Other cell types have been shown to have their morphological differentiation controlled by the density of neighboring like-type cells as well as by their afferents, and so each of these variables will be modulated to determine their effects upon the differentiation of bipolar cell dendrites. Finally, a developmental transcriptome analysis of the retina will be conducted in these each of these recombinant inbred strains, and made available to the scientific community on-line at NerveNetwork. This will enable the direct mapping of variations in gene expression to genomic loci, thereby aiding in the identification of candidate genes underlying the above variations in bipolar and photoreceptor cell number, and the detection of correlations in gene expression to identify regulatory networks that participate in the production of individual types of bipolar or photoreceptor cells. These experiments will reveal the determinants of nerve cell number and morphology, clarifying our understanding of retinal development, as well as identifying gene polymorphisms that may contribute to retinal disease.

Public Health Relevance

This research program will identify the molecular and genetic determinants controlling the natural variation in nerve cell number, examining the populations of photoreceptors and bipolar cells. It will determine how this variation in afferent and target cell number modulates the dendritic morphology of the bipolar cell. It will, consequently, clarify the developmental events and their underlying mechanisms that produce the functional architecture and connectivity of the retina. These studies will contribute to our understanding of retinal development and degeneration, and will enlighten our approach in developing treatments for retinal disease, particularly where the latter seek to re- establish connectivity following cell replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019968-04
Application #
8396392
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Greenwell, Thomas
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$338,053
Indirect Cost
$110,053
Name
University of California Santa Barbara
Department
Neurosciences
Type
Organized Research Units
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
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Keeley, Patrick W; Zhou, Cuiqi; Lu, Lu et al. (2014) Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics. Proc Natl Acad Sci U S A 111:9295-300
Keeley, Patrick W; Whitney, Irene E; Madsen, Nils R et al. (2014) Independent genomic control of neuronal number across retinal cell types. Dev Cell 30:103-9
Keeley, Patrick W; Madsen, Nils R; St John, Ace J et al. (2014) Programmed cell death of retinal cone bipolar cells is independent of afferent or target control. Dev Biol 394:191-6
Whitney, Irene E; Keeley, Patrick W; St John, Ace J et al. (2014) Sox2 regulates cholinergic amacrine cell positioning and dendritic stratification in the retina. J Neurosci 34:10109-21
Reese, Benjamin E; Keeley, Patrick W (2014) Design principles and developmental mechanisms underlying retinal mosaics. Biol Rev Camb Philos Soc :
Keeley, Patrick W; Luna, Gabriel; Fariss, Robert N et al. (2013) Development and plasticity of outer retinal circuitry following genetic removal of horizontal cells. J Neurosci 33:17847-62
Chen, Shih-Kuo; Chew, Kylie S; McNeill, David S et al. (2013) Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment. Neuron 77:503-15
Keeley, Patrick W; Sliff, Buranee J; Lee, Sammy C S et al. (2012) Neuronal clustering and fasciculation phenotype in Dscam- and Bax-deficient mouse retinas. J Comp Neurol 520:1349-64
Lee, Sammy C S; Cowgill, Erin J; Al-Nabulsi, Ali et al. (2011) Homotypic regulation of neuronal morphology and connectivity in the mouse retina. J Neurosci 31:14126-33

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