Male-biased aganglionic megacolon in the TashT mouse model of Hirschsprung disease involves upregulation of p53 protein activity and Ddx3y gene expression
PLOS Genetics
Dhh ‐expressing Schwann cell precursors contribute to skin and cochlear melanocytes, but not to vestibular melanocytes
9. Cut at the anus to free the gastrointestinal tract. The stomach and cecum will allow keeping t... more 9. Cut at the anus to free the gastrointestinal tract. The stomach and cecum will allow keeping track of sample's orientation (Figure 1-step 6 and Video 1).
A new mechanism for Hirschsprung's disease involving the self-modulation of neural crest cell microenvironment
Gastrointestinal motility is controlled by the enteric nervous system (ENS), which is derived fro... more Gastrointestinal motility is controlled by the enteric nervous system (ENS), which is derived from neural crest cells (NCC) of vagal origin. These cells colonize the developing intestines rostrocaudally, and become organized in ganglia by the concerted action of migration, proliferation, survival and differentiation processes. Defective colonization results in aganglionosis in the colon and thus lethal constipation, as seen in Hirschsprung's disease (HSCR). In order to identify new genes involved in NCC development and ENS formation, we generated and characterized a new mouse model for HSCR named Holstein. This mutant line was obtained by random insertion of a Tyrosinase transgene in an albino background followed by a screen for pigmentation abnormalities. Homozygous Holstein mice are depigmented and succumb to megacolon around 3 weeks after birth. Analysis of embryonic guts using different markers (HuC/D, S100β, Sox10, Ki67 and caspase 3) and time-lapse imaging strongly suggest...
Background: Intestinal atresia is a rare congenital disorder with an incidence of 3/10 000 birth.... more Background: Intestinal atresia is a rare congenital disorder with an incidence of 3/10 000 birth. About one-third of patients have severe intestinal dysfunction after surgical repair. We examined whether prenatal gastrointestinal obstruction might effect on the myenteric plexus and account for subsequent functional disorders. Methodology/Principal Findings: We studied a rat model of surgically induced antenatal atresia, comparing intestinal samples from both sides of the obstruction and with healthy rat pups controls. Whole-mount preparations of the myenteric plexus were stained for choline acetyltransferase (ChAT) and nitric oxide synthase (nNOS). Quantitative reverse transcription PCR was used to analyze mRNAs for inflammatory markers. Functional motility and permeability analyses were performed in vitro. Phenotypic studies were also performed in 8 newborns with intestinal atresia. In the experimental model, the proportion of nNOS-immunoreactive neurons was similar in proximal and distal segments (6.764.6% vs 5.664.2%, p = 0.25), but proximal segments contained a higher proportion of ChAT-immunoreactive neurons (13.266.2% vs 7.564.3%, p = 0.005). Phenotypic changes were associated with a 100-fold lower concentration-dependent contractile response to carbachol and a 1.6-fold higher EFS-induced contractile response in proximal compared to distal segments. Transcellular (p = 0.002) but not paracellular permeability was increased. Comparison with controls showed that modifications involved not only proximal but also distal segments. Phenotypic studies in human atresia confirmed the changes in ChAT expression. Conclusion: Experimental atresia in fetal rat induces differential myenteric plexus phenotypical as well as functional changes (motility and permeability) between the two sides of the obstruction. Delineating these changes might help to identify markers predictive of motility dysfunction and to define guidelines for post-surgical care.
Postnatal changes in the enteric nervous system (ENS) are involved in the establishment of coloni... more Postnatal changes in the enteric nervous system (ENS) are involved in the establishment of colonic motility. In adult rats, butyrate induced neuroplastic changes in the ENS, leading to enhanced colonic motility. Whether butyrate can induce similar changes during the postnatal period remains unknown. Enemas (Na-butyrate) were performed daily in rat pups between postnatal day (PND) 7 and PND 17. Effects of butyrate were evaluated on morphological and histological parameters in the distal colon at PND 21. The neurochemical phenotype of colonic submucosal and myenteric neurons was analyzed using antibodies against Hu, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS). Colonic motility and neuromuscular transmission was assessed in vivo and ex vivo. Butyrate (2.5 mM) enemas had no impact on pup growth and histological parameters compared with control. Butyrate did not modify the number of Hu-immunoreactive (IR) neurons per ganglia. A significant increase in the ...
BACKGROUND & AIMS: Little is known about the environmental and nutritional regulation of the ente... more BACKGROUND & AIMS: Little is known about the environmental and nutritional regulation of the enteric nervous system (ENS), which controls gastrointestinal motility. Short-chain fatty acids (SCFAs) such as butyrate regulate colonic mucosa homeostasis and can modulate neuronal excitability. We investigated their effects on the ENS and colonic motility. METHODS: Effects of butyrate on the ENS were studied in colons of rats given a resistant starch diet (RSD) or intracecal perfusion of SCFAs. Effects of butyrate were also studied in primary cultures of ENS. The neurochemical phenotype of the ENS was analyzed with antibodies against Hu, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS) and by quantitative polymerase chain reaction. Signaling pathways involved were analyzed by pharmacologic and molecular biology methods. Colonic motility was assessed in vivo and ex vivo. RESULTS: In vivo and in vitro, RSD and butyrate significantly increased the proportion of ChAT-but not nNOS-immunoreactive myenteric neurons. Acetate and propionate did not reproduce the effects of butyrate. Enteric neurons expressed monocarboxylate transporter 2 (MCT2). Small interfering RNAs silenced MCT2 and prevented the increase in the proportion of ChAT-immunoreactive neurons induced by butyrate. Butyrate and trichostatin A increased histone H3 acetylation in enteric neurons. Effects of butyrate were prevented by inhibitors of the Src signaling pathway. RSD increased colonic transit, and butyrate increased the cholinergic-mediated colonic circular muscle contractile response ex vivo. CONCLUSION: Butyrate or histone deacetylase inhibitors might be used, along with nutritional approaches, to treat various gastrointestinal motility disorders associated with inhibition of colonic transit.
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Papers by Rodolphe Soret