These authors contributed equally to this work.
L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development
Version of Record online: 14 MAR 2011
© 2011 Blackwell Publishing Ltd
Neurogastroenterology & Motility
Volume 23, Issue 11, pages e510–e522, November 2011
How to Cite
Wallace, A. S., Tan, M. X., Schachner, M. and Anderson, R. B. (2011), L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development. Neurogastroenterology & Motility, 23: e510–e522. doi: 10.1111/j.1365-2982.2011.01692.x
- Issue online: 10 OCT 2011
- Version of Record online: 14 MAR 2011
- Received: 3 November 2010 Accepted for publication: 7 February 2011
- cell migration;
- enteric nervous system;
- Hirschsprung’s disease;
- neural crest
Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung’s disease. The high degree of phenotypic variability reported in Hirschsprung’s disease suggests the involvement of modifier genes.
Methods We used a two-locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest-derived cells in wholemount preparations of embryonic gut.
Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et-3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest-derived cells was significantly delayed in L1cam−/y; Et-3−/− and L1cam−/y;Ednrbsl/sl embryos.
Conclusions & Inferences We have identified the X-linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung’s disease.