| Research Abstract |
In children with congenital gut anomaly, developmental abnormality including somites or vertebral anomaly are oftern associated. Some explanations for these clinical associations include the theory that early embryological abnormality may cause many pediatric surgical gut diseases. In this study, we investigated possible developmental abnormalities in the key process of head-tail axis and somite formation (SOX10, PAX3, Shh, Wnt, RET) in the early embryogenesis of pediatric surgical diseases.
In research of anorectal malformations (ARM), we studied the distribution pattern of retinoic acid receptors (RARs) in ARM murine embryos induced by overdose of all-trans retinoic acid, Over 98% of the embryos administered ATRA had ARM ; The RAR-alpha was found equally in the epithelium of hindgut-tailgut in normal embryos on E11.5. However, it was absent in the hindgut in the ARM embryos. Impaired distribution of RAR-alpha in the hindgut-tailgut on E11.5 succeedingly resulted in the incomplete part
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itioning of the cloaca and the rectourethral or rectocloacal fistula on E14.0. Overdose ATRA affected the distal hindgut development by directly disrupting the retinoid-mediated signalling pathway.
In addition to anorectal malformations, we investigated ret gene expression in animal models for congenital aganglionosis and children with Hirschsprung Is diasease. In experimental studies, renal agenesis or severe dysgenesis has been described in homozygously mutated mice for the ret or gdnf gene in addition to the lack of enteric ganglia. In humans, association with renal and other urinary tract diseases are exceptional in patients with congenital aganglionosis. The variation and discrepancy of the phenotypic expression of the disease between humans and mice or between kidney and gut also supports the presence of other genetic and/or environmental determinants in addition to RET/GDNF/NTN mutational patterns. These may depend upon differing threshold values for GDNF/NTN-Ret signal transduction in species, organ, gender and environmental factors in which the mother and fetus accidentally encounter during pregnancy. Less
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