PUBLICATION
Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas
- Authors
- Esni, F., Ghosh, B., Biankin, A.V., Lin, J.W., Albert, M.A., Yu, X., MacDonald, R.J., Civin, C.I., Real, F.X., Pack, M.A., Ball, D.W., and Leach, S.D.
- ID
- ZDB-PUB-040804-1
- Date
- 2004
- Source
- Development (Cambridge, England) 131(17): 4213-4224 (Journal)
- Registered Authors
- Leach, Steven D., Pack, Michael
- Keywords
- Zebrafish, Mouse, Pancreatic, Exocrine, Embryo, p48
- MeSH Terms
-
- Adenoviridae/genetics
- Animals
- COS Cells
- Cell Differentiation
- Endoderm/metabolism
- Gene Expression Regulation, Developmental*
- Gene Transfer Techniques
- Genes, Reporter
- Green Fluorescent Proteins
- In Situ Hybridization
- Lentivirus/genetics
- Luciferases/metabolism
- Luminescent Proteins/metabolism
- Membrane Proteins/metabolism
- Membrane Proteins/physiology*
- Mice
- Microscopy, Confocal
- Microscopy, Fluorescence
- Models, Biological
- Pancreas
- Plasmids/metabolism
- Promoter Regions, Genetic
- RNA, Messenger/metabolism
- Receptors, Notch
- Time Factors
- Transcription Factors/metabolism*
- Transfection
- Transgenes
- Zebrafish
- PubMed
- 15280211 Full text @ Development
Citation
Esni, F., Ghosh, B., Biankin, A.V., Lin, J.W., Albert, M.A., Yu, X., MacDonald, R.J., Civin, C.I., Real, F.X., Pack, M.A., Ball, D.W., and Leach, S.D. (2004) Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development (Cambridge, England). 131(17):4213-4224.
Abstract
Notch signaling regulates cell fate decisions in a variety of adult and embryonic tissues, and represents a characteristic feature of exocrine pancreatic cancer. In developing mouse pancreas, targeted inactivation of Notch pathway components has defined a role for Notch in regulating early endocrine differentiation, but has been less informative with respect to a possible role for Notch in regulating subsequent exocrine differentiation events. Here, we show that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. In developing mouse pancreas, the Notch target gene Hes1 is co-expressed with Ptf1-P48 in exocrine precursor cells, but not in differentiated amylase-positive acinar cells. Using lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds, we found that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf1-P48 expression, in a cell-autonomous manner. Ectopic Notch activation also delays acinar cell differentiation in developing zebrafish pancreas. Further evidence of a role for endogenous Notch in regulating exocrine pancreatic differentiation was provided by examination of zebrafish embryos with homozygous mindbomb mutations, in which Notch signaling is disrupted. mindbomb-deficient embryos display accelerated differentiation of exocrine pancreas relative to wild-type clutchmate controls. A similar phenotype was induced by expression of a dominant-negative Suppressor of Hairless [Su(H)] construct, confirming that Notch actively represses acinar cell differentiation during zebrafish pancreatic development. Using transient transfection assays involving a Ptf1-responsive reporter gene, we further demonstrate that Notch and Notch/Su(H) target genes directly inhibit Ptf1 activity, independent of changes in expression of Ptf1 component proteins. These results define a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping