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Abstract
Familial Dysautonomia (FD; Hereditary Sensory Autonomic Neuropathy; HSAN III) manifests from a failure in development of the peripheral sensory and autonomic nervous systems. The disease results from a point mutation in the IKBKAP gene, which encodes the IKAP protein, whose function is still unresolved in the developing nervous system. Since the neurons most severely depleted in the disease derive from the neural crest, and in light of data identifying a role for IKAP in cell motility and migration, it has been suggested that FD results from a disruption in neural crest migration. To determine the function of IKAP during development of the nervous system, we (1) first determined the spatial-temporal pattern of IKAP expression in the developing peripheral nervous system, from the onset of neural crest migration through the period of programmed cell death in the dorsal root ganglia, and (2) using RNAi, reduced expression of IKBKAP mRNA in the neural crest lineage throughout the process of dorsal root ganglia (DRG) development in chick embryos in ovo. Here we demonstrate that IKAP is not expressed by neural crest cells and instead is expressed as neurons differentiate both in the CNS and PNS, thus the devastation of the PNS in FD could not be due to disruptions in neural crest motility or migration. In addition, we show that alterations in the levels of IKAP, through both gain and loss of function studies, perturbs neuronal polarity, neuronal differentiation and survival. Thus IKAP plays pleiotropic roles in both the peripheral and central nervous systems.
Highlights
Familial Dysautonomia (FD) is an autosomal recessive disease whose hallmarks are decreased pain and temperature sensation, a dysfunctional autonomic nervous system marked by cardiac instability, vomiting crises, and renal failure [1]
The central and peripheral nervous systems express the lowest levels of wild type IKBKAP mRNA and these are the tissues most negatively impacted in the disease [5,6]
FD devastates the sensory neurons in the dorsal root ganglia and yet no careful temporal examination of IKBKAP expression in the developing DRG or PNS has been conducted
Summary
Familial Dysautonomia (FD) is an autosomal recessive disease whose hallmarks are decreased pain and temperature sensation, a dysfunctional autonomic nervous system marked by cardiac instability, vomiting crises, and renal failure [1]. Continued depletion of peripheral neurons continues throughout life and results in the progressive degeneration of sensory and sympathetic function. 3 mutations in the IKBKAP gene have been identified, the mutation in .99.5% of patients is in a splice acceptor site in intron 20 and results in variable skipping of exon 20, a presumed frameshift, and production of a mutant mRNA [4,5,6]. FD tissues express both wild-type and mutant IKBKAP mRNA, the ratios vary depending upon the tissue type. The central and peripheral nervous systems express the lowest levels of wild type IKBKAP mRNA and these are the tissues most negatively impacted in the disease [5,6]
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