Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.
Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6(Delta endo)) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on beta cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6(Delta panc)) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6(Delta panc) animals survived to adulthood. HNF6(Delta panc) pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6(Delta panc) pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology.
Zhang
Hongjie
H
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-0475, USA.
Ables
Elizabeth Tweedie
ET
Pope
Christine F
CF
Washington
M Kay
MK
Hipkens
Susan
S
Means
Anna L
AL
Path
Gunter
G
Seufert
Jochen
J
Costa
Robert H
RH
Leiter
Andrew B
AB
Magnuson
Mark A
MA
Gannon
Maureen
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004848:Epithelium / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018390:Gene Targeting; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010183:Pancreatic Ducts / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C407737:Neurog3 protein, mouse; C496606:Onecut1 protein, mouse