The development of colon innervation in trisomy 16 mice and Hirschsprungs disease

Li, Ji Cheng; Mi, Kai; Zhou, Jingjing; Lc, Busch; Kühnel, Wolfgang

doi:10.3748/wjg.v7.i1.16

Cited by 17 publications

(10 citation statements)

References 45 publications

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“…Among these are the Ednrb-null mouse [9] that we used in this study but also the endothelin-3 ligand-deficient mouse [10], the Hoxb5 dominant negative conditional (Cre-Lox) transgenic genotype [22], erbB2/nestin-Cre conditional mutant mouse [23], the Dom spontaneous mutant mouse [24], a conditional β1 integrin knockout mouse [25], trisomy 16 mice [26,27], and mice deficient in the c-ret proto-oncogene [28]. In addition, the endothelin B receptor-deficient rat (spotting lethal rat) [29–31] and the fmc/fmc (familial megacecum and colon) rat [32] also display a phenotype that mimics HD.…”

Section: Discussionmentioning

confidence: 99%

Murine model of Hirschsprung-associated enterocolitis. I: Phenotypic characterization with development of a histopathologic grading system

Cheng

Dhall

Zhao

et al. 2010

Journal of Pediatric Surgery

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Purpose The aim of the study was to characterize enterocolitis in the Ednrb-null (Ednrb−/−) mouse with aganglionosis of the colon and to develop and validate a semiquantitative histopathologic grading system to assess enterocolitis. Methods We isolated colon and ileal specimens of Ednrb−/− and control mice (Ednrb+/+) and performed histochemical staining (H&E) on tissue sections. After establishing inflammation grading criteria, 2 blinded pathologists independently assessed the severity and depth of inflammation of proximal colon segments on 2 separate occasions. Interclass correlations (ICCs) and coefficient of variation (CV) were calculated to determine interrater and intrarater agreement. We then prospectively applied the enterocolitis grading system to Ednrb−/− mice that became clinically ill. A cohort of Ednrb−/− mice were observed until they developed clinical illness, at which time they were euthanized and had multiple organ homogenates cultured for bacteria, and colon and small bowel were histopathologically graded for enterocolitis. Spearman’s rank correlations comparing enterocolitis scores with level of bacteremia were performed. Results Intra- and interrater ICCs of the histologic scoring system were satisfactory (0.61 and 0.94, respectively), as were intra- and interrater CVs (18% and 9%, respectively). Of the Ednrb−/− mice, 65% developed bacteremia. Those with bacteremia had significantly higher enterocolitis scores than those without bacteremia (P < .01). Ednrb−/− mice that developed bacteremia showed a strong positive correlation between total enterocolitis scores and number of bacterial colony forming units in peritoneal lavage, liver, kidney, and aerobic spleen. Conclusions The Ednrb−/− mouse with aganglionosis develops enterocolitis and has features similar to Hirschsprung-associated enterocolitis in humans. Our grading system is a reliable way to assess enterocolitis. By performing microsurgical pull-through, we can now perform controlled, hypothesis-driven, mechanistic studies to evaluate etiologic factors affecting enterocolitis in the Ednrb−/− mouse.

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Section: Discussionmentioning

confidence: 99%

Murine model of Hirschsprung-associated enterocolitis. I: Phenotypic characterization with development of a histopathologic grading system

Cheng

Dhall

Zhao

et al. 2010

Journal of Pediatric Surgery

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“…The rodent models can be used to study HD and its associated enterocolitis include the Ednrb-null mouse [2,3], piebaldlethal mouse [4,5], and the endothelin receptor B-deficient rat (spotting lethal rat) [6-8]. Additional mutant rodent models that can now be used to study HD include the Endothelin-3 ligand-deficient mouse [9], the Hoxb5 dominant negative conditional (Cre-Lox) transgenic genotype [10], erbB2/nestin-Cre conditional mutant mouse [11], the Dom spontaneous mutant mouse [12], a conditional β -1 integrin knockout mouse [13], trisomy 16 mice [14,15], and mice deficient in the c-ret proto-oncogene [16], and the fmc/ fmc (familial megacecum and colon) rat [17] that also display a phenotype that mimics HD.…”

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confidence: 99%

Murine model of Hirschsprung-associated enterocolitis II: Surgical correction of aganglionosis does not eliminate enterocolitis

Zhao¹,

Dhall²,

Cheng³

et al. 2010

Journal of Pediatric Surgery

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Background Hirschsprung disease (HD) results from aganglionosis of the colon, is linked to acute and chronic enterocolitis (known as Hirschsprung-associated enterocolitis) despite successful corrective surgery, and can lead to bacteremia and even death. The genetic and molecular mechanisms underlying these disorders are largely unknown. Methods We developed a microsurgical corrective pull-through procedure in mice, and applied that to Ednrb−/− mice, which manifest aganglionic megacolon that is very similar to HD. Wild-type littermates (Ednrb+/+) also underwent identical surgery. At prespecified time points postoperatively, mice were sacrificed, and histopathologic analyses of intestinal inflammation were performed. Mice of both genotypes were sacrificed after the postoperative recovery period to determine if corrective surgery itself caused inflammation. Stooling patterns were assessed as well to determine if intestinal function normalized after surgery. Results: There was no difference in histopathological enterocolitis scores after recovery from surgery. Stooling patterns in Ednrb−/− and Ednrb+/+ mice were similar postoperatively, suggesting normalization of intestinal function. However, with time, approximately 40% of Ednrb−/− mice developed clinical illness consistent with enterocolitis. No control (Ednrb+/+) mice developed clinical enterocolitis. Histopathological enterocolitis scores in the 40% of Ednrb−/− mice that developed clinical enterocolitis postoperatively were significantly worse than those of healthy postoperative Ednrb−/− mice. In contrast, none of the Ednrb+/+ control mice exhibited postoperative long-term inflammation. Conclusions Microsurgical pull-through operation in Ednrb−/− mice produces a mouse model that closely resembles key features of Hirschsprung-associated enterocolitis, enabling controlled study of genetic and molecular mechanisms in Ednrb−/− mice and other genotypes that produce similar phenotypes.

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“…The absence of intramural intestinal ganglia of Meissner and Auerbach results in poor coordination of propulsive movement, and hence functional intestinal obstruction. Patients were treated surgically with removal of the affected intestine [1][2][3][4] . In 1994, two major genes associated with HD were recognized.…”

Section: Introductionmentioning

confidence: 99%

Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung’s disease

Duan

Zhang²,

Li³

2003

WJG

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AIM:To investigate the mutation of EDNRB gene and EDN-3 gene in sporadic Hirschsprung's disease (HD) in Chinese population. METHODS:Genomic DNA was extracted from bowel tissues of 34 unrelated HD patients which were removed by surgery. Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 of EDN-3 gene were amplified by polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP). RESULTS:EDNRB mutations were detected in 2 of the 13 short-segment HD. One mutant was in the exon 3, the other was in the exon 6. EDN-3 mutation was detected in one of the 13 short-segment HD and in the exon 2. Both EDNRB and EDN-3 mutations were detected in one short-segment HD. No mutations were detected in the ordinary or longsegment HD.

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The development of colon innervation in trisomy 16 mice and Hirschsprungs disease

Cited by 17 publications

References 45 publications

Murine model of Hirschsprung-associated enterocolitis. I: Phenotypic characterization with development of a histopathologic grading system

Murine model of Hirschsprung-associated enterocolitis. I: Phenotypic characterization with development of a histopathologic grading system

Murine model of Hirschsprung-associated enterocolitis II: Surgical correction of aganglionosis does not eliminate enterocolitis

Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung’s disease

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