title: LIM homeodomain transcription factor Isl1 directs normal pyloric development by targeting Gata3.
abstract: BACKGROUND
  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 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.
  
  
  RESULTS
  Examination 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.
  
  
  CONCLUSIONS
  This 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.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Li
authors.forename: Jirong
authors.initials: J
authors.lastname: Pan
authors.forename: Chao
authors.initials: C
authors.lastname: Wei
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China. dryancui@yahoo.com.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D016207:Cytokines; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009132:Muscles / Q000473:pathology; D011708:Pylorus / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000199:Actins; D016207:Cytokines; D050990:GATA3 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D055758:SOX9 Transcription Factor; D014157:Transcription Factors; C113178:Grem1 protein, mouse; C484469:Nkx2-5 protein, mouse; C544013:alpha-smooth muscle actin, mouse; C063843:insulin gene enhancer binding protein Isl-1