Asymmetrically-Expressed Genes in Developing Human Cerebrum

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): 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. Among the most important functional specializations of the human cerebral cortex are the perisylvian language regions, which are asymetric in humans. Surprisingly little is known about the biological processes that underlie this functional and structural compartmentilization of language 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 began to screen a large number of potentially asymmetric expreesed genes using microarray technology, followed by confirmation using in situ hybridization. This process of confirmation is ongoing and we will continue to identlfy 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 peri-sylvian language regions, as well as those expressed asymmetrically in adult posterior peri-sylvian regions. Representational Difference Analysis-coupled microarray screening will be used to identify genes differentially expressed within these language related regions, which will be confirmed using Northern Blotting and In Situ hybridization. A subset of differentially expressed genes 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 homologus human structures. This work will inform the study of human neurodevelopmental disorders that are related to speech and language, such as autism and development dyslexia, as well as probe the utility and limitations of animal models for these and related neurodevelopmental disorders.