Wnt/beta-catenin signaling is required for development of the exocrine pancreas.
BACKGROUND
Beta-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of beta-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that beta-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of beta-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of beta-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of beta-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed beta-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis.


RESULTS
Pdx1-cre floxed beta-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed beta-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the beta-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas.


CONCLUSIONS
We conclude that beta-catenin expression is required for development of the exocrine pancreas, but is not required for development of the endocrine compartment. In contrast, beta-catenin/Wnt signaling appears to be critical for proliferation of PTF1+ nascent acinar cells and may also function, in part, to maintain an undifferentiated state in exocrine/acinar cell precursors. Finally, beta-catenin may be required to maintain positional identity of the pancreatic endoderm along the anterior-posterior axis. This data is consistent with the findings of frequent beta-catenin mutations in carcinomas of acinar cell lineage seen in humans.
Wells
James M
JM
Department of Developmental Biology, Cincinnati Children's Hospital Research 45267, Cincinnati, OH 45267, USA. james.wells@cchmc.org
Esni
Farzad
F
Boivin
Gregory P
GP
Aronow
Bruce J
BJ
Stuart
William
W
Combs
Chelsea
C
Sklenka
Angela
A
Leach
Steven D
SD
Lowy
Andrew M
AM
D000818:Animals; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000166:cytology / Q000196:embryology*; D040081:Protein Array Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
D018398:Homeodomain Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; C084010:pancreatic and duodenal homeobox 1 protein