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 #
5R01EY019968-05
Application #
8594252
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Greenwell, Thomas
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$319,634
Indirect Cost
$103,634
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
Reese, Benjamin E (2018) Axon Terminal Arbors of Retinal Horizontal Cells Lose Control. Front Neural Circuits 12:82
Sankaran, Mathangi; Keeley, Patrick W; He, Li et al. (2018) Dopaminergic amacrine cell number, plexus density, and dopamine content in the mouse retina: Strain differences and effects of Bax gene disruption. Exp Eye Res 177:208-212
Keeley, Patrick W; Reese, Benjamin E (2018) The somal patterning of the AII amacrine cell mosaic in the mouse retina is indistinguishable from random simulations matched for density and constrained by soma size. Vis Neurosci 35:E003
Stincic, Todd L; Keeley, Patrick W; Reese, Benjamin E et al. (2018) Bistratified starburst amacrine cells in Sox2 conditional knockout mouse retina display ON and OFF responses. J Neurophysiol 120:2121-2129
Kautzman, Amanda G; Keeley, Patrick W; Borhanian, Sarra et al. (2018) Genetic Control of Rod Bipolar Cell Number in the Mouse Retina. Front Neurosci 12:285
Keeley, Patrick W; Reese, Benjamin E (2018) DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina. J Comp Neurol 526:467-479
Kautzman, Amanda G; Keeley, Patrick W; Nahmou, Michael M et al. (2018) Sox2 regulates astrocytic and vascular development in the retina. Glia 66:623-636
Kautzman, Amanda G; Keeley, Patrick W; Ackley, Caroline R et al. (2018) Xkr8 Modulates Bipolar Cell Number in the Mouse Retina. Front Neurosci 12:876
Keeley, Patrick W; Whitney, Irene E; Reese, Benjamin E (2017) Genomic Control of Retinal Cell Number: Challenges, Protocol, and Results. Methods Mol Biol 1488:365-390
Puller, Christian; Arbogast, Patrick; Keeley, Patrick W et al. (2017) Dendritic stratification differs among retinal OFF bipolar cell types in the absence of rod photoreceptors. PLoS One 12:e0173455

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