Malformations of cortical development are increasingly recognized as an important cause of epilepsy, developmental delay and mental retardation. The major aim of the proposed project is to determine the molecular mechanisms that control development of upper layer neurons in the cerebral cortex.
We discovered that overproduction of upper-layer neurons at expense of deep layer neurons is the major characteristic of the cerebral cortex phenotype in the mouse model of Mowat-Wilson syndrome, Sip1 mutant mice. We identified Foxo1 transcription factor and Neurotrophin3 growth factor as immediate targets of Sip1 in the cortex. We will specifically analyze the function of Foxo1/3/4 genes and NT3 gene in the mouse cortical development as well as in the genesis of Mowat-Wilson syndrome. We will inactivate and overexpress these genes specifically in the cortex and study which aspects of the Sip1 mutant phenotype and Mowat-Wilson syndrome are controlled by Foxo1 and NT3 genes. Additionally we will identify molecular pathways down-stream of these genes.
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