title: Context-specific α- to-β-cell reprogramming by forced Pdx1 expression.
abstract: Using single transcription factors to reprogram cells could produce important insights into the epigenetic mechanisms that direct normal differentiation, or counter inappropriate plasticity, or even provide new ways of manipulating normal ontogeny in vitro to control lineage diversification and differentiation. We enforced Pdx1 expression from the Neurogenin-3-expressing endocrine commitment point onward and found during the embryonic period a minor increased β-cell allocation with accompanying reduced α-cell numbers. More surprisingly, almost all remaining Pdx1-containing glucagon/Arx-producing cells underwent a fairly rapid conversion at postnatal stages, through glucagon-insulin double positivity, to a state indistinguishable from normal β cells, resulting in complete α-cell absence. This α-to-β conversion was not caused by activating Pdx1 in the later glucagon-expressing state. Our findings reveal that Pdx1 can work single-handedly as a potent context-dependent autonomous reprogramming agent, and suggest a postnatal differentiation evaluation stage involved in normal endocrine maturation.
authors.affiliation: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Boyer
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005934:Glucagon; D018398:Homeodomain Proteins; D007328:Insulin; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein