title: NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas.
abstract: In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting beta-cells of the pancreatic islets. As successful generation of insulin-producing cells in vitro could constitute a cure for diabetes, recent studies have explored the molecular program that underlies beta-cell formation. From these studies, the homeodomain transcription factor NKX6.1 has proven to be a key player. In Nkx6.1 mutants, beta-cell numbers are selectively reduced, while other islet cell types develop normally. However, the molecular events downstream of NKX6.1, as well as the molecular pathways that ensure residual beta-cell formation in the absence of NKX6.1 are largely unknown. Here, we show that the Nkx6.1 paralog, Nkx6.2, is expressed during pancreas development and partially compensates for NKX6.1 function. Surprisingly, our analysis of Nkx6 compound mutant mice revealed a previously unrecognized requirement for NKX6 activity in alpha-cell formation. This finding suggests a more general role for NKX6 factors in endocrine cell differentiation than formerly suggested. Similar to NKX6 factors, the transcription factor MYT1 has recently been shown to regulate alpha- as well as beta-cell development. We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway.
authors.affiliation: Department of Developmental and Cell Biology, University of California at Irvine, 4203 McGaugh Hall, Irvine, CA 92697-2300, USA.
authors.forename: Korinna D
authors.initials: KD
authors.lastname: Henseleit
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Nelson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kuhlbrodt
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000196:embryology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C489726:Myt1 protein, mouse; C407737:Neurog3 protein, mouse; C491328:Nkx6-1 protein, mouse; C436827:Nkx6.2 protein, vertebrate