Abstract
BackgroundAbnormalities in pyloric development or in contractile function of the pylorus cause reflux of duodenal contents into the stomach and increase the risk of gastric metaplasia and cancer. Abnormalities of the pyloric region are also linked to congenital defects such as the relatively common neonatal hypertrophic pyloric stenosis, and primary duodenogastric reflux. Therefore, understanding pyloric development is of great clinical relevance. Here, we investigated the role of the LIM homeodomain transcription factor Isl1 in pyloric development.ResultsExamination of Isl1 expression in developing mouse stomach by immunohistochemistry, whole mount in situ hybridization and real-time quantitative PCR demonstrated that Isl1 is highly expressed in developing mouse stomach, principally in the smooth muscle layer of the pylorus. Isl1 expression was also examined by immunofluorescence in human hypertrophic pyloric stenosis where the majority of smooth muscle cells were found to express Isl1. Isl1 function in embryonic stomach development was investigated utilizing a tamoxifen-inducible Isl1 knockout mouse model. Isl1 deficiency led to nearly complete absence of the pyloric outer longitudinal muscle layer at embryonic day 18.5, which is consistent with Gata3 null mouse phenotype. Chromatin immunoprecipitation, luciferase assays, and electrophoretic mobility shift assays revealed that Isl1 ensures normal pyloric development by directly targeting Gata3.ConclusionsThis study demonstrates that the Isl1-Gata3 transcription regulatory axis is essential for normal pyloric development. These findings are highly clinically relevant and may help to better understand pathways leading to pyloric disease.
Highlights
Abnormalities in pyloric development or in contractile function of the pylorus cause reflux of duodenal contents into the stomach and increase the risk of gastric metaplasia and cancer
Insulin gene enhancer protein (Isl1) is expressed in embryonic mouse stomach We examined Isl1 mRNA levels in embryonic mouse stomach by real-time quantitative PCR (RT-qPCR) and whole mount in situ hybridization (WISH)
Isl1-positive cells are co-expressed with α-smooth muscle actin in embryonic mouse stomach To see whether Isl1 expression was related to smooth muscle development of the pylorus, we examined the expression of Isl1 and the earliest smooth muscle marker α-SMA using immunofluorescence
Summary
Abnormalities in pyloric development or in contractile function of the pylorus cause reflux of duodenal contents into the stomach and increase the risk of gastric metaplasia and cancer. Abnormalities of the pyloric region are linked to congenital defects such as the relatively common neonatal hypertrophic pyloric stenosis, and primary duodenogastric reflux. The gut becomes patterned along the anterior-posterior, dorsal-ventral, leftright, and radial axes. The gut tube consists of the foregut, midgut, and hindgut along its anterior-posterior axis [4,5]. The foregut gives rise to the esophagus, stomach, liver, lungs, and pancreas. The midgut forms the small intestine and the hindgut develops into the large intestine [1,5,6,7,8]
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