Overview of Interests
My research program is focused on developmental genetics of neural crest and the contributions of these cells to development of the autonomic nervous system. Our primary focus area has been the enteric neural crest and identification of genes that influence the extent of innervation in mouse models of Hirschsprung disease (HSCR). To investigate neural crest derivatives, we use both genetic (modifier screens and linkage analysis) and developmental (analysis of neural crest derivatives in embryos) approaches. Our genome scan to identify modifiers of aganglionosis in the Sox10 mouse model of HSCR has successfully localized five loci that influence this phenotype, two of these genes have been definitively identified. This modifier project is ongoing to characterize the genes responsible for the remaining modifier loci and define the mechanisms of gene interaction during population of the enteric nervous system by neural crest stem cells. To investigate lineage diversification (neuronal vs glial) in the peripheral nervous system and gain a better understanding of processes that go awry in neural crest disorders like HSCR, we have established lines of transgenic mice driving expression of fluorescent proteins in the neuronal and glial linages of the peripheral nervous system. While our initial incentive was to visualize migration in enteric neural crest, these transgenes reveal migration of neural crest progenitors giving rise to innervation in other systems that are affected in children with neurocristopathies including the heart, lung, and urogential systems. We are expanding our studies to investigate the development of innervation in these systems and aim to identify commonalities of gene expression and signaling pathways that are shared among neural crest in these organ systems.
Our research is highly relevant to the goals of the Kennedy Center and the NICHD. Our genetic studies of modifiers are revealing new genes that are essential to the processes of neural crest stem cell migration. Understanding the genes and signaling pathways that promote or repress these processes are essential to efforts that aim to use neural crest stem cells to repopulate the peripheral nervous system. Moreover our transgenic analysis in normal and mutant mice offers significant opportunities to understand how neural crest progenitors give rise to autonomic innervation in multiple organ systems.
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