Furthering knowledge of the molecular basis of human cognitive specializations is of critical importance for developing an improved understanding and treatments for a wide variety of neurodevelopmental and neurodegenerative diseases in humans. 1 of the most important functional specializations of the human cerebral cortex is that of the perisylvian cortex, which among other functions is involved in language. In the majority of humans, this is accompanied by anatomical asymmetry of the right and left cerebral hemispheres. Surprisingly, little is known about the biological processes that underlie the development of perisylvian cortical regions in humans, their lateralization, and presence in other potential model organisms. This proposal is a renewal of our previously funded work, in which we recently identified a number of potentially asymmetrically expressed genes using various screening techniques, followed by confirmation using in situ hybridization. The process of confirmation is ongoing and we plan to continue to try to identify and characterize genes that are differentially expressed by the developing left and right cerebral hemispheres in the developing human brain. Based on data obtained in our completed studies and Preliminary Results, we have modified our initial studies in this proposal to include the identification of genes enriched in anterior and posterior perisylvian language regions. Putative differentially expressed genes which will be confirmed using Northern Blotting and In Situ hybridization. A subset of differentially expressed genes, including LMO4 and other members of its interacting transcriptional regulatory complex will be further studied in detail at different developmental stages and in different brain regions at the RNA and protein level to probe their functional relationship with other brain structures and circuits. Cross species comparisons, in mice and non-human primate species will be performed to investigate the evolutionary conservation of genes that are enriched in language-related cortex, or asymmetrically expressed in the developing human cerebral cortex. This will provide insight into the potential role of these genes in the development and evolution of language and related human cognitive specializations and the relationship of these regions in lower species to homologous human structures. All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, as well as probe the utility and limitations of animal models for these disorders.
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