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
Duque, Alvaro; Krsnik, Zeljka; Kostović, Ivica et al. (2016) Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates. Proc Natl Acad Sci U S A 113:9892-7
Benoit, Jamie; Ayoub, Albert; Rakic, Pasko (2016) Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation. Brain Struct Funct 221:3963-3978
Morozov, Yury M; Sun, Yu-Yo; Kuan, Chia-Yi et al. (2016) Alteration of SLP2-like immunolabeling in mitochondria signifies early cellular damage in developing and adult mouse brain. Eur J Neurosci 43:245-57
Rash, Brian G; Ackman, James B; Rakic, Pasko (2016) Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation. Sci Adv 2:e1501733
Ayoub, Albert E; Rakic, Pasko (2015) Neuronal misplacement in schizophrenia. Biol Psychiatry 77:925-6
Benoit, Jamie; Ayoub, Albert E; Rakic, Pasko (2015) Transcriptomics of critical period of visual cortical plasticity in mice. Proc Natl Acad Sci U S A 112:8094-9
Radonjić, Nevena V; Ayoub, Albert E; Memi, Fani et al. (2014) Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche. Cell Rep 9:2139-51
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

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