The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse.
OBJECTIVE
A number of hereditary polycystic diseases are associated with formation of cysts within the pancreatic ducts. The cysts result from abnormal tubulogenesis, but how normal pancreatic duct development is controlled remains poorly understood. Here, we investigate the transcriptional mechanisms that control pancreatic duct development by addressing the role of the transcription factor hepatocyte nuclear factor (HNF)-6.


METHODS
Using immunostaining, we have determined the expression pattern of HNF-6 in pancreatic ducts during mouse development. Hnf6 null mice at various stages of development were studied by immunolocalization methods to assess the morphology, differentiation, and proliferation status of ductal cells. The expression of genes involved in hereditary polycystic diseases was determined by real-time, reverse-transcription polymerase chain reaction (RT-PCR).


RESULTS
We show that HNF-6 is expressed in the pancreatic duct epithelium throughout development and that, in the absence of HNF-6, duct morphogenesis is perturbed. Although development of the intercalated ducts is normal, cysts appear within the interlobular and intralobular ducts. This is associated with abnormal development of primary cilia at the apical pole of the duct cells and with reduced expression of a set of genes involved in polycystic diseases, namely those coding for HNF-1beta and for the cilium-associated proteins polyductin/fibrocystin and cystin.


CONCLUSIONS
We identify HNF-6 as the first transcriptional regulator of pancreatic duct development and reveal the existence of different regulatory mechanisms in distinct duct compartments. HNF-6 controls a network of genes involved in cilium formation and in hereditary polycystic diseases. Finally, HNF-6 deficiency represents a genetically defined model of pancreatic cystic disease.
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Institute of Cellular Pathology, Brussels, Belgium.
Christophe E
CE
Pierreux
Aurélie V
AV
Poll
Caroline R
CR
Kemp
Frédéric
F
Clotman
Miguel A
MA
Maestro
Sabine
S
Cordi
Jorge
J
Ferrer
Luc
L
Leyns
Guy G
GG
Rousseau
Frédéric P
FP
Lemaigre
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D010182:Pancreatic Diseases / Q000235:genetics; D010183:Pancreatic Ducts / Q000196:embryology / Q000254:growth & development*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D051559:Hepatocyte Nuclear Factor 6; C496606:Onecut1 protein, mouse