Skip Navigation



Human Molecular Genetics Advance Access published online on August 4, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh243
© 2004 by Oxford University Press
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/19/2289    most recent
ddh243v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Cantrell, V. A.
Right arrow Articles by Southard-Smith, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cantrell, V. A.
Right arrow Articles by Southard-Smith, E. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Article

Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease

V. Ashley Cantrell 1, Sarah E. Owens 1, Ronald L. Chandler 1, David C. Airey 2, Kevin M. Bradley 1, Jeffrey R. Smith 1, E. Michelle Southard-Smith 1*

1 Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, 529 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232-0275
2 Department of Pharmacology, Vanderbilt University School of Medicine, 8148-A Medical Research Building III, 465 21st Avenue South, Nashville, TN 37232-8548

* To whom correspondence should be addressed. E-mail: michelle.southard-smith{at}vanderbilt.edu.


  Abstract

Cumulative evidence suggests Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. One of the essential genes for this process is the neural crest transcription factor Sox10. Sox10Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric aganglionosis that are analogous to the variable aganglionosis seen in human HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine if known HSCR susceptibility loci are acting as modifiers of Sox10 we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and Sox10 mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system (ENS) in mouse models and suggests this interaction could contribute to the epistatic network that produces variation between patients with aganglionosis.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
M.-M. Garcia-Barcelo, C. S.-m. Tang, E. S.-w. Ngan, V. C.-h. Lui, Y. Chen, M.-t. So, T. Y.-y. Leon, X.-p. Miao, C. K.-y. Shum, F.-q. Liu, et al.
Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
PNAS, February 24, 2009; 106(8): 2694 - 2699.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
N. Bondurand, D. Natarajan, A. Barlow, N. Thapar, and V. Pachnis
Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling
Development, May 15, 2006; 133(10): 2075 - 2086.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. E. Owens, K. W. Broman, T. Wiltshire, J. B. Elmore, K. M. Bradley, J. R. Smith, and E. M. Southard-Smith
Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease
Hum. Mol. Genet., June 1, 2005; 14(11): 1549 - 1558.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
I. K. Quigley, J. L. Manuel, R. A. Roberts, R. J. Nuckels, E. R. Herrington, E. L. MacDonald, and D. M. Parichy
Evolutionary diversification of pigment pattern in Danio fishes: differential fms dependence and stripe loss in D. albolineatus
Development, January 1, 2005; 132(1): 89 - 104.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.