Int. J. Dev. Biol. 57: 391 - 398 (2013)
doi: 10.1387/ijdb.120048ah
© UPV/EHU Press

The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut

Andrew M. Holland*,1, Sonia Garcia1, Gaetano Naselli2, Raymond J. MacDonald3 and Leonard C. Harrison2

1Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia, 2Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia and 3University of Texas Southwestern Medical Center, Dallas, TX, USA

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 Brunner’s 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 Barrett’s esophagus.

Keywords:

Pdx1, Cdx2, parahox, Brunner’s gland, tTA

*Corresponding author e-mail: AMHolland35@gmail.com