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Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia


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.

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Correspondence to Akihiko Yoshimura.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of Sprouty2-deficient mice. (PDF 1923 kb)

Supplementary Fig. 2

Body weight and intestinal pseudo-obstruction of Sprouty2-deficient mice. (PDF 3100 kb)

Supplementary Fig. 3

Contraction force of small intestine in response to CCh. (PDF 1313 kb)

Supplementary Fig. 4

ENS hyperplasia in Sprouty2-deficient mice. (PDF 1587 kb)

Supplementary Fig. 5

Immunoblotting for phosphorylation of Erk1/Erk2 and Akt in response to GDNF in neural and muscle layers of the colon. (PDF 110 kb)

Supplementary Fig. 6

Anti-GDNF–corrected ENS hyperplasia of Sprouty2-deficient mice. (PDF 6017 kb)

Supplementary Fig. 7

Chimeric Ret-Fc protein corrected ENS hyperplasia of Sprouty2-deficient mice. (PDF 6315 kb)

Supplementary Methods (PDF 33 kb)

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Figure 1: Esophageal achalasia and intestinal pseudo-obstruction in Sprouty2-deficient mice.
Figure 2: ENS hyperplasia in Sprouty2-deficient mice.