title: Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development.
abstract: Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used aNeurog3-Creallele to ablateNkx2.2, one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3+endocrine progenitor lineage (Nkx2.2△endo). Remarkably, many essential components of the β cell transcriptional network that were down-regulated in theNkx2.2KOmice, were maintained in theNkx2.2△endomice - yet theNkx2.2△endomice displayed defective β cell differentiation and recapitulated theNkx2.2KOphenotype. This suggests that Nkx2.2 is not only required in the early pancreatic progenitors, but has additional essential activities within the endocrine progenitor population. Consistently, we demonstrate Nkx2.2 functions as an integral component of a modular regulatory program to correctly specify pancreatic islet cell fates.
authors.affiliation: Naomi Berrie Diabetes Institute, Columbia University Medical School, New York, Columbia.|Department of Genetics and Development, Columbia University Medical School, New York, Columbia.|Genetics and Development Doctoral Program, Columbia University Medical School, New York, Columbia.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Churchill
authors.affiliation: Naomi Berrie Diabetes Institute, Columbia University Medical School, New York, Columbia.|Department of Genetics and Development, Columbia University Medical School, New York, Columbia.|Nutritional and Metabolic Biology Doctoral Program, Columbia University Medical School, New York, Columbia.
authors.forename: Giselle Dominguez
authors.initials: GD
authors.lastname: Gutiérrez
authors.affiliation: Naomi Berrie Diabetes Institute, Columbia University Medical School, New York, Columbia.|Department of Genetics and Development, Columbia University Medical School, New York, Columbia.|The Integrated Graduate Program in Cellular, Molecular and Biomedical Studies, Columbia University Medical School, New York, Columbia.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Singer
authors.affiliation: Barbara Davis Center, University of Colorado, Denver, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Lorberbaum
authors.affiliation: Barbara Davis Center, University of Colorado, Denver, United States.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Fischer
authors.affiliation: Naomi Berrie Diabetes Institute, Columbia University Medical School, New York, Columbia.|Department of Genetics and Development, Columbia University Medical School, New York, Columbia.|Genetics and Development Doctoral Program, Columbia University Medical School, New York, Columbia.|Nutritional and Metabolic Biology Doctoral Program, Columbia University Medical School, New York, Columbia.|The Integrated Graduate Program in Cellular, Molecular and Biomedical Studies, Columbia University Medical School, New York, Columbia.|Barbara Davis Center, University of Colorado, Denver, United States.
authors.forename: Lori
authors.identifier: 0000-0003-2832-1319
authors.initials: L
authors.lastname: Sussel
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C000715630:nkx2.2b protein, zebrafish
keywords: Transcriptional networks; beta cells; developmental biology; mouse; pancreatic islet; stem cells