Histochemical study of Dom mouse: A model for Waardenburg-Hirschsprung's phenotype

Antonella Brizzolara, Michele Torre, Anna Favre, Alessio Pini Prato, Renata Bocciardi, Giuseppe Martucciello

Research output: Contribution to journalArticle

Abstract

Background/Purpose The spontaneous mouse mutant Dominant megacolon (Dom) represents the model of the Waardenburg-Hirschsprung's disease, a syndromic pathology, characterized by the association of pigmentation defects (PD), deafness, and Hirschsprung's disease (HD). The defect in Dom mouse is caused by a spontaneous mutation of the gene encoding the Sry-related transcription factor Sox10. This mutation affects several aspects of neural crest development leading to combined enteric innervation and pigmentation defects, both in mouse and human. The purpose of this report is to define, by enzymo-histochemical techniques routinely used for the diagnosis of human Hirschsprung's disease (AChE, LDH, NADPH-diaphorase), the innervative patterns of the affected gut. Methods Fifty-four siblings of Heterozygous Dom/+ mice underwent autopsy and were genotyped by direct sequencing of polymerase chain reaction (PCR) products for Sox10 mutations. The enteric nervous system of all the mice was studied by histochemical techniques indicated above. Results Genotyping showed that 43 mice were Dom/+ and 11 were Wild type +/+. Wild-type +/+ mice were used as control. The correspondence between genotype and at least 1 phenotypic aspect (PD or dysganglionosis) was present in 93% of cases (41 of 43). Among the Dom/+ mice, dysganglionosis was present in 79% of cases and PD in 90% of cases. Moreover, among Dom/+ mice, excluding those whose mantle was not evaluated as dead just after birth, PD and dysganglionosis (complete phenotype) were present in 68% of cases. Conclusions The histochemical methods that we used proved to be useful for identification of different aganglionic (AG), hypoganglionic (HG), and normoganglionic segments of Dom/+ mouse gut studied in longitudinal sections. Unlike humans, control mice (Wild type +/+) presented a rich component of AChE nerve fibers, whereas Dom/+ mice with dysganglionosis presented a decrease in AChE-positive nerve fibers. These data confirm the variable phenotypic penetrance in heterozygous mice. Because dysganglionosis in this animal model (Dom/+) was evident in 79% of cases (AG or HG), we concluded that Dom mice could represent important models for further experimental studies.

Original languageEnglish
Pages (from-to)1098-1103
Number of pages6
JournalJournal of Pediatric Surgery
Volume39
Issue number7
DOIs
Publication statusPublished - Jul 2004

Fingerprint

Megacolon
Phenotype
Pigmentation
Hirschsprung Disease
Nerve Fibers
Mutation
sry Genes
Enteric Nervous System
NADPH Dehydrogenase
Penetrance
Neural Crest
Deafness

Keywords

  • animal models
  • Dom mouse
  • Hirschsprung's
  • histochemistry
  • Sox10
  • Waardenburg

ASJC Scopus subject areas

  • Surgery

Cite this

Histochemical study of Dom mouse : A model for Waardenburg-Hirschsprung's phenotype. / Brizzolara, Antonella; Torre, Michele; Favre, Anna; Prato, Alessio Pini; Bocciardi, Renata; Martucciello, Giuseppe.

In: Journal of Pediatric Surgery, Vol. 39, No. 7, 07.2004, p. 1098-1103.

Research output: Contribution to journalArticle

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N2 - Background/Purpose The spontaneous mouse mutant Dominant megacolon (Dom) represents the model of the Waardenburg-Hirschsprung's disease, a syndromic pathology, characterized by the association of pigmentation defects (PD), deafness, and Hirschsprung's disease (HD). The defect in Dom mouse is caused by a spontaneous mutation of the gene encoding the Sry-related transcription factor Sox10. This mutation affects several aspects of neural crest development leading to combined enteric innervation and pigmentation defects, both in mouse and human. The purpose of this report is to define, by enzymo-histochemical techniques routinely used for the diagnosis of human Hirschsprung's disease (AChE, LDH, NADPH-diaphorase), the innervative patterns of the affected gut. Methods Fifty-four siblings of Heterozygous Dom/+ mice underwent autopsy and were genotyped by direct sequencing of polymerase chain reaction (PCR) products for Sox10 mutations. The enteric nervous system of all the mice was studied by histochemical techniques indicated above. Results Genotyping showed that 43 mice were Dom/+ and 11 were Wild type +/+. Wild-type +/+ mice were used as control. The correspondence between genotype and at least 1 phenotypic aspect (PD or dysganglionosis) was present in 93% of cases (41 of 43). Among the Dom/+ mice, dysganglionosis was present in 79% of cases and PD in 90% of cases. Moreover, among Dom/+ mice, excluding those whose mantle was not evaluated as dead just after birth, PD and dysganglionosis (complete phenotype) were present in 68% of cases. Conclusions The histochemical methods that we used proved to be useful for identification of different aganglionic (AG), hypoganglionic (HG), and normoganglionic segments of Dom/+ mouse gut studied in longitudinal sections. Unlike humans, control mice (Wild type +/+) presented a rich component of AChE nerve fibers, whereas Dom/+ mice with dysganglionosis presented a decrease in AChE-positive nerve fibers. These data confirm the variable phenotypic penetrance in heterozygous mice. Because dysganglionosis in this animal model (Dom/+) was evident in 79% of cases (AG or HG), we concluded that Dom mice could represent important models for further experimental studies.

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