title: Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors.
abstract: Early in pancreatic development, epithelial cells of pancreatic buds function as primary multipotent progenitor cells (1°MPC) that specify all three pancreatic cell lineages, i.e., endocrine, acinar and duct. Bipotent "Trunk" progenitors derived from 1°MPC are implicated in directly regulating the specification of endocrine progenitors. It is unclear if this specification process is initiated in the 1°MPC where some 1°MPC become competent for later specification of endocrine progenitors. Previously we reported that in Pdx1tTA/+;tetOMafA (bigenic) mice inducing expression of transcription factor MafA in Pdx1-expressing (Pdx1+) cells throughout embryonic development inhibited the proliferation and differentiation of 1°MPC cells, resulting in reduced pancreatic mass and endocrine cells by embryonic day (E) 17.5. Induction of the transgene only until E12.5 in Pdx1+ 1°MPC was sufficient for this inhibition of endocrine cells and pancreatic mass at E17.5. However, by birth (P0), as we now report, such bigenic pups had significantly increased pancreatic and endocrine volumes with endocrine clusters containing all pancreatic endocrine cell types. The increase in endocrine cells resulted from a higher proliferation of tubular epithelial cells expressing the progenitor marker Glut2 in E17.5 bigenic embryos and increased number of Neurog3-expressing cells at E19.5. A BrdU-labeling study demonstrated that inhibiting proliferation of 1°MPC by forced MafA-expression did not lead to retention of those progenitors in E17.5 tubular epithelium. Our data suggest that the forced MafA expression in the 1°MPC inhibits their competency to specify endocrine progenitors only until E17.5, and after that compensatory proliferation of tubular epithelium gives rise to a distinct pool of endocrine progenitors. Thus, these bigenic mice provide a novel way to characterize the competency of 1°MPC for their ability to specify endocrine progenitors, a critical limitation in our understanding of endocrine differentiation.
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.|Division of Anatomy, Bio-imaging and Neuro-cell Science, Jichi Univerisity, Tochigi, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishimura
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Archana
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ilham
authors.initials: I
authors.lastname: El Khattabi
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Wanzhu
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D055098:Endocrine Cells / Q000378:metabolism / Q000502:physiology; D004703:Endocrine System / Q000378:metabolism / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051273:Glucose Transporter Type 2; D051473:Maf Transcription Factors, Large; D009419:Nerve Tissue Proteins; C485160:Mafa protein, mouse; C407737:Neurog3 protein, mouse