Submitted on November 28, 2007
Accepted on February 6, 2008
DISTURBANCES OF COLONIC MOTILITY IN MOUSE MODELS OF HIRSCHSPRUNG'S DISEASE
Rachael Rosemarie Roberts1*, Joel Charles Bornstein2, Annette J Bergner3, and Heather M Young4
1 Physiology, University of Melbourne, Melbourne, Victoria, Australia
2 Physiology, University of Melbourne, Parkville, Victoria, Australia
3 Dept of Anatomy & Cell Biology, Univeristy of Melbourne, Melbourne, Victoria, Australia
4 Dept of Anatomy & Cell Biology, University of Melbourne, Melbourne, Victoria, Australia
* To whom correspondence should be addressed. E-mail: r.roberts1{at}pgrad.unimelb.edu.au.
Mutations in genes encoding members of the GDNF and endothelin-3 (Et-3) signaling pathways can cause Hirschsprung's disease, a congenital condition associated with an absence of enteric neurons in the distal gut. GDNF signals through Ret, a receptor tyrosine kinase, and Et-3 signals through endothelin receptor B (Ednrb). The effects of Gdnf, Ret and Et-3 haploinsufficiency and a null mutation in Et-3 , on spontaneous motility patterns in adult and developing mice were investigated. Video recordings were used to construct spatiotemporal maps of spontaneous contractile patterns in colon from post-natal and adult mice in vitro. In Ret +/- and Et-3 +/- mice, which have normal numbers of enteric neurons, colonic migrating motor complexes (CMMCs) displayed similar properties under control conditions and following inhibition of nitric oxide synthase (NOS) activity to wild-type mice. In the colon of Gdnf +/- mice and in the ganglionic region of Et-3 -/- mice, there was a 50-60% reduction in myenteric neuron number. In Gdnf +/- mice, CMMCs were present, but abnormal, and the proportion of myenteric neurons containing NOS was not different from wild-type mice. In the ganglionic region of post-natal Et-3 -/- mice, CMMCs were absent, and the proportion of myenteric neurons containing NOS was over 100% higher than in wild-type mice. Thus impairments in spontaneous motility patterns in the colon of Gdnf +/- mice and in the ganglionic region of Et-3 -/- mice are correlated with a reduction in myenteric neuron density.
