Sonic hedgehog and bone morphogenetic protein 4 expressions in the hindgut region of murine embryos with anorectal malformations

The aim of this study was to determine the possible role of the retinoid-mediated signaling pathway in the pathogenesis of anorectal malformations (ARM). The authors investigated whether all-trans retinoic acid (ATRA) affects the expression pattern of Sonic hedgehog (Shh) and Bone morphogenetic prot...

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Bibliographic Details
Published in:Journal of pediatric surgery 2004-02, Vol.39 (2), p.170
Main Authors: Sasaki, Yasunari, Iwai, Naomi, Tsuda, Tomoki, Kimura, Osamu
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - chemically induced
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
Anal Canal - abnormalities
Anal Canal - embryology
Anal Canal - metabolism
Animals
Bone Morphogenetic Protein 4
Bone Morphogenetic Proteins - biosynthesis
Bone Morphogenetic Proteins - genetics
Cell Differentiation
Cloaca - abnormalities
Epithelium - metabolism
Female
Fetal Death - chemically induced
Gene Expression Regulation, Developmental
Gestational Age
Hedgehog Proteins
Mesoderm - metabolism
Mice
Mice, Inbred ICR
Morphogenesis - genetics
Organ Specificity
Pregnancy
Rectum - abnormalities
Rectum - embryology
Rectum - metabolism
Signal Transduction
Tail - abnormalities
Trans-Activators - biosynthesis
Trans-Activators - genetics
Tretinoin - toxicity
Urethra - embryology
Urethra - metabolism
Urinary Bladder - embryology
Urinary Bladder - metabolism
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Summary:The aim of this study was to determine the possible role of the retinoid-mediated signaling pathway in the pathogenesis of anorectal malformations (ARM). The authors investigated whether all-trans retinoic acid (ATRA) affects the expression pattern of Sonic hedgehog (Shh) and Bone morphogenetic protein 4 (BMP4), which play important roles in anorectal morphogenesis in vertebrates. Pregnant ICR strain mice were fed 100 mg/kg of ATRA on the ninth gestational day (E9). Embryos with or without administration of ATRA were obtained from the uteri between E12 and E16 and were fixed immediately in a 4% paraformaldehyde solution. Frozen sections were evaluated for concentric layers around the endodermal epithelium by H&E and immunohistochemistry using antibodies created specifically to act against Shh and BMP4. More than 95% of the embryos administered ATRA had ARM; rectoprostatic urethral fistula, rectocloacal fistula, and short tail were the most frequent anomalies in the mouse embryos. On E14, normal mouse embryos had normal rectum and anus in which the epithelium of the anorectum was positive for Shh, and the mesenchyme was positive for BMP4. In the ARM embryos, however, the epithelium of the anorectum was negative for Shh, and the mesenchyme was also negative for BMP4. In normal hindgut development, Shh from the epithelium induces BMP4 expression in the mesenchyme, which differentiates into the lamina propria and the submucosa. In ARM embryos, expressions of Shh and BMP4 could not be found in those regions of the hindgut. Therefore, these findings indicate that Shh and BMP4, which appear to play a crucial role in organogenesis of the hindgut, were disturbed in the cell signaling pathway between the epithelium and the mesenchyme layers.
ISSN:1531-5037