Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome

Abstract

BackgroundRett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice.Methods Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples.ResultsFirst we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice.ConclusionsIn summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40348-016-0065-3) contains supplementary material, which is available to authorized users.

Rett syndrome: think outside the (skull) box

“…At the histological scale, Mecp2 -null mice displayed a shorter colon with severe changes in its epithelium similar to those observed in colitis and abnormal localization of key membrane proteins 31 . However, conditional deletion of Mecp2 from intestinal tissue using the villin promoter, an actin binding protein expressed mainly in the microvilli of the epithelium of the gut, does not reproduce the Mecp2 -null GI phenotype 31 . Since the conditional Mecp2-KO in non-neuronal cells does not display any body-weight decrease compared with the control group 8 , these symptoms may have a neural origin.…”

Reprogramming of the intestinal epithelial-immune cell interactome during SARS-CoV-2 infection

“…Furthermore, several colon-specific functions were related to extracellular matrix organization and integrin cell surface interactions, suggesting decreased interactions involved in focal adhesion and intestinal tissue polarization uniquely in the colon ( Supplementary Figure 9A ). The only function uniquely overrepresented in the ileum was transcriptional regulation by MECP2 ( Supplementary Figure 9A ), whose expression has been shown to play a role in intestinal morphology and function (Millar-Büchner et al, 2016).…”

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

“…As the diets were similar between the Rett and control subjects, these results suggest that altered MECP2 levels in the digestive tract may alter the intestinal environment and thus microbe growth. In fact, it was recently shown that mice with loss of Mecp2 expression solely in the intestine have severe colonic epithelial defects (Millar-Büchner et al, 2016). As there is direct signaling from the gut to the brain, extension of these gut/microbiome studies should be extended to Bird Mecp2 −/+ deficient female deletion mice and would thus provide critical insights for female Rett patients.…”