A mouse model for monitoring islet cell genesis and developing therapies for diabetes.
Transient expression of the transcription factor neurogenin-3 marks progenitor cells in the pancreas as they differentiate into islet cells. We developed a transgenic mouse line in which the surrogate markers secreted alkaline phosphatase (SeAP) and enhanced green florescent protein (EGFP) can be used to monitor neurogenin-3 expression, and thus islet cell genesis. In transgenic embryos, cells expressing EGFP lined the pancreatic ducts. SeAP was readily detectable in embryos, in the media of cultured embryonic pancreases and in the serum of adult animals. Treatment with the γ-secretase inhibitor DAPT, which blocks Notch signaling, enhanced SeAP secretion rates and increased the number of EGFP-expressing cells as assayed by fluorescence-activated cell sorting (FACS) and immunohistochemistry in cultured pancreases from embryos at embryonic day 11.5, but not in pancreases harvested 1 day later. By contrast, treatment with growth differentiation factor 11 (GDF11) reduced SeAP secretion rates. In adult mice, partial pancreatectomy decreased, whereas duct ligation increased, circulating SeAP levels. This model will be useful for studying signals involved in islet cell genesis in vivo and developing therapies that induce this process.
Diabetes Center, University of California San Francisco, San Francisco, CA 94143-0534, USA.
Yoshinori
Y
Shimajiri
Yasuhiro
Y
Kosaka
David W
DW
Scheel
Francis C
FC
Lynn
Nina
N
Kishimoto
Juehu
J
Wang
Shuhong
S
Zhao
Michael S
MS
German
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019070:Cell Lineage; D003920:Diabetes Mellitus / Q000628:therapy*; D005333:Fetus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D055412:Growth Differentiation Factors / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D038081:Organogenesis; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes / Q000235:genetics
D000469:Alkaline Phosphatase; D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D049452:Green Fluorescent Proteins; D055412:Growth Differentiation Factors; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; C119153:Gdf11 protein, mouse; C407737:Neurog3 protein, mouse; C485184:enhanced green fluorescent protein