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.
View: Text | PDF
Research Article Gastroenterology

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

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

×

Figure 3

Reduced expression of Ret causes aganglionosis in the distal colon in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Reduced expression of Ret causes aganglionosis in the distal colon in vi...
(A) Dosage-dependent effects of Ret on the incidence and severity of aganglionosis in the gut. AChE staining of the colon (left panels), images of kidneys (middle panels), and neurofilament (NF) labeling of latissimus dorsi (LD) muscles (right panels) from Ret+/+, Ret9/9, Retfl/–, Ret9/–, and Ret–/– newborn (P0) mice are shown. Ret expression levels (Ret exp.) were determined by real-time RT-PCR (see Figure 2). (B) Representative pictures of the gastrointestinal tracts of Ret9/– mice revealed by AChE histochemistry are shown. We refer to the reticulate pattern of enteric innervation with no aganglionic segment as normal. Cases were classified as severe when the length of the aganglionic segments in the entire colon exceeded 3 mm. Cases intermediate between normal and severe were classified as moderate. Scale bar: 200 μm in A; 100 μm in B.