title: Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas.
abstract: Notch signaling regulates numerous developmental processes, often acting either to promote one cell fate over another or else to inhibit differentiation altogether. In the embryonic pancreas, Notch and its target gene Hes1 are thought to inhibit endocrine and exocrine specification. Although differentiated cells appear to downregulate Hes1, it is unknown whether Hes1 expression marks multipotent progenitors, or else lineage-restricted precursors. Moreover, although rare cells of the adult pancreas express Hes1, it is unknown whether these represent a specialized progenitor-like population. To address these issues, we developed a mouse Hes1(CreERT2) knock-in allele to inducibly mark Hes1(+) cells and their descendants. We find that Hes1 expression in the early embryonic pancreas identifies multipotent, Notch-responsive progenitors, differentiation of which is blocked by activated Notch. In later embryogenesis, Hes1 marks exocrine-restricted progenitors, in which activated Notch promotes ductal differentiation. In the adult pancreas, Hes1 expression persists in rare differentiated cells, particularly terminal duct or centroacinar cells. Although we find that Hes1(+) cells in the resting or injured pancreas do not behave as adult stem cells for insulin-producing beta (β)-cells, Hes1 expression does identify stem cells throughout the small and large intestine. Together, these studies clarify the roles of Notch and Hes1 in the developing and adult pancreas, and open new avenues to study Notch signaling in this and other tissues.
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kopinke
authors.forename: Marisa
authors.initials: M
authors.lastname: Brailsford
authors.forename: Jill E
authors.initials: JE
authors.lastname: Shea
authors.forename: Rebecca
authors.initials: R
authors.lastname: Leavitt
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: L Charles
authors.initials: LC
authors.lastname: Murtaugh
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000196:embryology / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse