In vitro and in vivo functional analysis of Ikbkap in Familial Dysautonomia

Northwestern University At Chicago, Evanston IL

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Abstract

Sympathetic nervous system (SNS) abnormalities have been implicated in a wide variety of congenital, neurodegenerative and neoplastic diseases. However, few molecules have been specifically identified in the pathogenesis of human SNS-related diseases. Familial Dysautonomia (FD;Riley-Day Syndrome;hereditary sensory and autonomic neuropathy, type 3;HSAN3;OMIM 223900) is one of five well-recognized genetic disorders affecting the sensory and autonomic nervous systems. A highly conserved point mutation located in the donor splice site of intron 20 of the human IKBKAP gene has been identified in >99.5% of FD cases. The mutation weakens the intron-exon boundary definition between exon 20 and 21, leading to exon-20 deficient transcripts and premature truncation of the translated protein. The abnormal splicing preferentially occurs in the nervous system, but the cause and functional significance is not well understood. To better understand the function of IKAP, the protein encoded by the IKBKAP gene, in FD and specifically its role in sympathetic and sensory neuron development, I will 1) characterize the effects of IKAP knockdown by utilizing RNA interference (RNAi) in primary sympathetic and sensory neuron culture and 2) generate and characterized a conditional IKBKAP knockout (cKO) mouse to explore the cell autonomous function of IKAP in SNS development. These studies will test the hypothesis that loss of IKAP in developing neurons can lead to cell autonomous abnormalities involving neuron migration, differentiation, survival and/or target tissue innervation.