We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line–derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.
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We thank T. Yoshioka, M. Ohtsu, E. Fujimoto and N. Kinoshita for technical assistance, M. Takahashi (Nagoya University) for discussion and comments and Y. Nishi for manuscript preparation. This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports and Culture of Japan; the Haraguchi Memorial Foundation; the Yamanouchi Foundation for Research on Metabolic Disorders; the Takeda Science Foundation; the Kato Memorial Foundation and the Uehara Memorial Foundation.
The authors declare no competing financial interests.
Generation of Sprouty2-deficient mice. (PDF 1923 kb)
Body weight and intestinal pseudo-obstruction of Sprouty2-deficient mice. (PDF 3100 kb)
Contraction force of small intestine in response to CCh. (PDF 1313 kb)
ENS hyperplasia in Sprouty2-deficient mice. (PDF 1587 kb)
Immunoblotting for phosphorylation of Erk1/Erk2 and Akt in response to GDNF in neural and muscle layers of the colon. (PDF 110 kb)
Anti-GDNF–corrected ENS hyperplasia of Sprouty2-deficient mice. (PDF 6017 kb)
Chimeric Ret-Fc protein corrected ENS hyperplasia of Sprouty2-deficient mice. (PDF 6315 kb)
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