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Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice
Toshihiro Uesaka, … , Shigenobu Yonemura, Hideki Enomoto
Toshihiro Uesaka, … , Shigenobu Yonemura, Hideki Enomoto
Published April 15, 2008
Citation Information: J Clin Invest. 2008;118(5):1890-1898. https://doi.org/10.1172/JCI34425.
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Research Article Gastroenterology

Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice

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Abstract

Mutations in the RET gene are the primary cause of Hirschsprung disease (HSCR), or congenital intestinal aganglionosis. However, how RET malfunction leads to HSCR is not known. It has recently been shown that glial cell line–derived neurotrophic factor (GDNF) family receptor α1 (GFRα1), which binds to GDNF and activates RET, is essential for the survival of enteric neurons. In this study, we investigated Ret regulation of enteric neuron survival and its potential involvement in HSCR. Conditional ablation of Ret in postmigratory enteric neurons caused widespread neuronal death in the colon, which led to colonic aganglionosis. To further examine this finding, we generated a mouse model for HSCR by reducing Ret expression levels. These mice recapitulated the genetic and phenotypic features of HSCR and developed colonic aganglionosis due to impaired migration and successive death of enteric neural crest–derived cells. Death of enteric neurons was also induced in the colon, where reduction of Ret expression was induced after the period of enteric neural crest cell migration, indicating that diminished Ret expression directly affected the survival of colonic neurons. Thus, enteric neuron survival is sensitive to RET dosage, and cell death is potentially involved in the etiology of HSCR.

Authors

Toshihiro Uesaka, Mayumi Nagashimada, Shigenobu Yonemura, Hideki Enomoto

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Figure 2

Quantitative analysis of Ret expression in enteric neurons.

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Quantitative analysis of Ret expression in enteric neurons.
   
(A) Expr...
(A) Expression of Ret mRNA in the enteric plexus of small intestine at P0 was determined by real-time RT-PCR using human or mouse Ret primers. To estimate the total number of neurons in individual tissue samples, expression levels of βIII-tubulin mRNA were also determined. Results for each group was normalized to β-actin values. Error bars indicate SEM (n = 3). (B) Expression of RET protein in the enteric plexus of P0 Ret+/+, Retfl/fl, Ret9/9, Ret+/–, Retfl/–, and Ret9/– mice. Protein extracts were immunoprecipitated with anti-RET antibody (C-19; Santa Cruz Biotechnology Inc.). Detection of mouse or human RET was done using antibody against the extracellular domain of RET (R&D Systems; or 12EXY, Santa Cruz Biotechnology Inc.). Results are shown separately for mouse RET (+/+ and +/–: left) and for human Ret9 (flox/flox, Ret9/Ret9, flox/–, and Ret9/–; right). Values for quantitated band intensities (sum of RET 170- and 150-kDA bands) are indicated below each lane (expression levels of RET in +/+ and flox/flox lanes were assigned as 100 for mouse and human RET, respectively). (C) The ratio of the glycosylated (170-kDA band) to the immature (150-kDa band) form is shown as mean ± SEM. *P < 0.05, statistically significant difference compared with Ret9/–.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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