title: The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut.
abstract: The homeobox gene Pdx1 is a key regulator of pancreas and foregut development. Loss of Pdx1 expression results in pancreas agenesis and impaired development of the gastro-duodenal domain including Brunners glands. We previously demonstrated a key role for Pdx1 in maintaining the integrity and function of insulin-secreting beta cells in the adult pancreas. In the present study, we aimed to determine if expression of Pdx1 is required to maintain the cellular identity of the gastro-duodenal domain in adult mice. Immunohistological studies were performed in a mouse model in which expression of Pdx1 was conditionally repressed with the doxycycline-responsive tetracycline transactivator system. Mice in which Pdx1 was chronically repressed developed hamartomas in the gastro-duodenal domain. These lesions appeared to arise from ectopic foci of anteriorized cells, consistent with a localised anterior homeotic shift. They emerge with the intercalation of tissue between the anteriorized and normal domains and appear strikingly similar to lesions in the colon of mice heterozygous for another Parahox gene, Cdx2. Continuing expression of Pdx1 into adult life is required to maintain regional cellular identity in the adult foregut, specifically at the gastro-duodenal boundary. Loss of Pdx1 expression leads to anterior transformation and intercalary regeneration of ectopic tissue. We propose a model in which the posterior dominance of classical Hox genes is mirrored by the Parahox genes, providing further evidence of the functional conservation of the Parahox genes. These findings may have implications for further understanding the molecular basis of gastro-duodenal metaplasia and gastro-intestinal transformations such as Barretts esophagus.
authors.affiliation: Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia. AMHolland35@gmail.com
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Holland
authors.forename: Sonia
authors.initials: S
authors.lastname: Garcia
authors.forename: Gaetano
authors.initials: G
authors.lastname: Naselli
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Macdonald
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D004065:Digestive System Abnormalities / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000166:cytology / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism*; D006222:Hamartoma / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D013270:Stomach / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein