Strain-specific alleles of <i>Phox2B</i> differentially modify <i>Sox10^Dom</i> aganglionosis

Description

Hirschsprung disease (HSCR) is characterized by a lack of enteric ganglia in a variable portion of the distal bowel. The complex inheritance pattern of this disorder has led researchers to focus on genetic effects other than the putative disease mutation. Mouse models provide a controlled background for these types of studies. <i>Sox10</i> is an essential gene for the development of the enteric nervous system (ENS). <i>Sox10^Dom</i> mice on a mixed genetic background exhibit the variable aganglionosis seen in HSCR cases. Congenic lines of <i>Sox10^Dom</i> mice on distinct inbred genetic backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe), differ in penetrance and extent of aganglionosis. A linkage screen for modifiers of <i>Sox10^Dom</i> aganglionosis was undertaken in a large B6 X C3Fe F₂ population. Several potential modifier regions were identified, with the most significant located on chromosome five (<i>Sox10m3</i>). The most relevant candidate gene in this region was <i>Phox2B</i>, an essential factor in autonomic neurogenesis.<p>
This goal of this dissertation was to understand the developmental differences between the congenic <i>Sox10^Dom</i> lines and how <i>Phox2B</i> impacts those differences. This study involved exploring differential expression of <i>Phox2B</i>, genetic variation at this locus between inbred strains, and the effects of different alleles of <i>Phox2B</i> on ENS development. The results suggest that <i>Phox2B</i> is differentially expressed between the B6 and C3Fe strains. The putative differences in expression are most likely due to genetic variation at key regulatory regions that are associated with aganglionic severity across multiple inbred strains. Strain-specific alleles at <i>Phox2B</i> modulate the effect of the <i>Sox10^Dom</i> mutation on ENS development.<p>
The work presented in this dissertation confirms the identification of <i>Phox2B</i> as the <i>Sox10m3</i> modifier and demonstrates the effects of genetic background on complex phenotypes such as HSCR-related aganglionosis. By extending the principles used in this work to other genes and inbred strains, a greater understanding of the pathogenesis of HSCR can be achieved.

Links & Downloads

1. http://etd.library.vanderbilt.edu/available/etd-12162010-140102/

Tags

Human Genetics

Additional Fields

Identifer	oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12162010-140102
Date	15 February 2011
Creators	Walters, Lauren Colleen
Contributors	Dr. E. Michelle Southard-Smith, Ph.D., Dr. David W. Threadgill, Ph.D., Dr. David Airey, Ph.D., Dr. Jennifer A. Kearney, Ph.D., Dr. Douglas P. Mortlock, Ph.D.
Publisher	VANDERBILT
Source Sets	Vanderbilt University Theses
Language	English
Detected Language	English
Type	text
Format	application/pdf
Source	http://etd.library.vanderbilt.edu/available/etd-12162010-140102/
Rights	restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.