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Genomic exploration of the peripheral nervous system: Identification of candidate genes for neuroblastoma, hearing loss, and other aspects of neuron biology and tumorigenesis

  • Author(s): Hackett, Christopher Sultan
  • Advisor(s): Weiss, William A
  • et al.
Abstract

Neuroblastoma is a deadly tumor derived from neuronal tissue for which the molecular drivers remain a mystery. Here we have applied classical genetics, analysis of expression quantitative trait loci (eQTL), and forward insertional mutagenesis to uncover novel pathways in the disease. We showed that liver arginase is a candidate susceptibility gene and interacts with component of the GABA pathway both genetically and biochemically to influence tumor susceptibility, and both of these pathways represent potential therapeutic targets. We then constructed a gene coexpression network in tumors and in sympathetic ganglia to explore novel genetic/functional interactions in both neuroblastoma and normal neurons. In particular, we used the coexpression network to identify novel candidate genes for several hereditary hearing loss loci. In a separate project, we focused on forward genetics utilizing the Sleeping Beauty insertional mutagenesis system. We developed a novel algorithm to predict local insertion site preferences of the vector, and show that the

transposon system does not cause widespread genomic instability. We then generated a novel transgenic line, TH-SB11, to drive tumors in the peripheral sympathetic nervous system. Finally, we explored methods to drive tumors in the mammary gland, and generated a novel knock-in line capable of driving high-level conditional transposase expression in any tissue. This work illustrates the genetic complexity of neuroblastoma,

and has identified novel functional pathways in the disease and a novel therapeutic target. In addition, this work lays the foundation for further gene discovery in neuroblastoma and other tumor types.

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