The main objective of this longstanding research program, which was voluntarily interrupted in 2008, remains the elucidation of principles governing prenatal development of the primate visual system. Accumulated evidence indicates that the developing human visual system has a number of anatomical, cellular and molecular features that are underdeveloped or absent in non-primate species. It is generally agreed that genes and transcription factors activated sequentially before birth specify these features, although no specific details are available. To shed light on these questions, we propose to perform a comprehensive analysis of gene expression by next generation sequencing in visual structures at different stages of development of the macaque monkey. We selected this Old World monkey as the main study subject because its visual system is remarkably similar to that in humans, and contains features that are underdeveloped or absent in non-primate species and thus cannot be studied in more common animal models. We propose to take advantage of our unique experience, access to the human material and the primate breeding colony at Yale as well as already collected tissue, to apply the methodological advances made in genetics and molecular biology to characterize and analyze development of these features. To obtain the most from the expensive animals and valuable tissue, we will study the entire system, from the retinal (Aim #1) via the thalamus (Aim #2) to the areas 17 and 18 of the visual cortex (Aim #3) including possible contribution from the subpial granular layer (Aim #4). At each level we will use immunocytochemistry, in situ hybridization, confocal microscopy and mRNA seq gene profiling following laser capture microdissection of selected populations of cells in human, macaque and mouse developing visual system. As a next step, we will carry out experimental studies in the developing macaque brain and supravital human embryonic brain tissue, including application of transneuronal tracers or lentiviral gene transfer, to identify molecular and cellula mechanisms involved in ontogenetic and phylogenetic emergence of these differences. Understanding the uniqueness of the primate visual system will provide an essential bridge between fundamental research on the visual system obtained from non-primate species and the primate and human emerging properties. These data have potential to benefit, research on primate anatomy, physiology and behavior as well as the neuropathology of normal and disordered human brain. Finally, taking advantage of the data from the macaque genome project, our findings may provide insight into genetic and acquired congenital errors of primate visual system development.

Public Health Relevance

In spite of the great similarity among all mammals, the visual system in humans and Old World primates contains some features that are absent and/or underdeveloped in non-primate species. We will use the most advanced methods to investigate the genetic origin and developmental mechanisms of these features that may provide new insights into disorders of human vision.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY002593-29
Application #
8761603
Study Section
Special Emphasis Panel (SPC)
Program Officer
Greenwell, Thomas
Project Start
1978-08-01
Project End
2018-08-31
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
29
Fiscal Year
2014
Total Cost
$777,535
Indirect Cost
$278,691
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Selemon, Lynn D; Ceritoglu, Can; Ratnanather, J Tilak et al. (2013) Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation. J Comp Neurol 521:1040-53
Selemon, Lynn D; Begovic, Anita; Rakic, Pasko (2009) Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages. J Comp Neurol 515:454-64
Rakic, Pasko (2007) The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Brain Res Rev 55:204-19
Sarkisian, Matthew R; Bartley, Christopher M; Chi, Hongbo et al. (2006) MEKK4 signaling regulates filamin expression and neuronal migration. Neuron 52:789-801
Kornack, D R; Rakic, P (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294:2127-30
Meissirel, C; Wikler, K C; Chalupa, L M et al. (1997) Early divergence of magnocellular and parvocellular functional subsystems in the embryonic primate visual system. Proc Natl Acad Sci U S A 94:5900-5
Wikler, K C; Rakic, P; Bhattacharyya, N et al. (1997) Early emergence of photoreceptor mosaicism in the primate retina revealed by a novel cone-specific monoclonal antibody. J Comp Neurol 377:500-8
Suner, I; Rakic, P (1996) Numerical relationship between neurons in the lateral geniculate nucleus and primary visual cortex in macaque monkeys. Vis Neurosci 13:585-90
Rapaport, D H; Rakic, P; LaVail, M M (1996) Spatiotemporal gradients of cell genesis in the primate retina. Perspect Dev Neurobiol 3:147-59
Mrzljak, L; Levey, A I; Rakic, P (1996) Selective expression of m2 muscarinic receptor in the parvocellular channel of the primate visual cortex. Proc Natl Acad Sci U S A 93:7337-40

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