title: Jagged1 is a competitive inhibitor of Notch signaling in the embryonic pancreas.
abstract: Pancreatic endocrine cells originate from precursors that express the transcription factor Neurogenin3 (Ngn3). Ngn3 expression is repressed by active Notch signaling. Accordingly, mice with Notch signaling pathway mutations display increased Ngn3 expression and endocrine cell lineage allocation. To determine how the Notch ligand Jagged1 (Jag1) functions during pancreas development, we deleted Jag1 in foregut endoderm and examined postnatal and embryonic endocrine cells and precursors. Postnatal Jag1 mutants display increased Ngn3 expression, alpha-cell mass, and endocrine cell percentage, similar to the early embryonic phenotype of Dll1 and Rbpj mutants. However, in sharp contrast to postnatal animals, Jag1-deficient embryos display increased expression of Notch transcriptional targets and decreased Ngn3 expression, resulting in reduced endocrine lineage allocation. Jag1 acts as an inhibitor of Notch signaling during embryonic pancreas development but an activator of Notch signaling postnatally. Expression of the Notch modifier Manic Fringe (Mfng) is limited to endocrine precursors, providing a possible explanation for the inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development.
authors.affiliation: Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Golson
authors.forename: John
authors.initials: J
authors.lastname: Le Lay
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.forename: Nuria
authors.initials: N
authors.lastname: Brämswig
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.forename: Rebecca
authors.initials: R
authors.lastname: Oakey
authors.forename: Catherine L
authors.initials: CL
authors.lastname: May
authors.forename: Peter
authors.initials: P
authors.lastname: White
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D019070:Cell Lineage; D055098:Endocrine Cells / Q000378:metabolism; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000196:embryology*; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C000606274:Jag1 protein, mouse; C407737:Neurog3 protein, mouse