title: Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage.
abstract: BACKGROUND
  Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented.Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals.
  
  
  RESULTS
  We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone.
  
  
  CONCLUSIONS
  Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.
authors: Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany.
authors: Simon
authors: S
authors: Kordowich
authors: Patrick
authors: P
authors: Collombat
authors: Ahmed
authors: A
authors: Mansouri
authors: Palle
authors: P
authors: Serup
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D054439:Ghrelin / Q000096:biosynthesis* / Q000235:genetics; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D000071841:PAX6 Transcription Factor; D050809:POU Domain Factors / Q000096:biosynthesis; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D013004:Somatostatin / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D029961:Zebrafish Proteins
chemical_list: C469265:ARX protein, mouse; D005136:Eye Proteins; D054439:Ghrelin; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D058228:Islet Amyloid Polypeptide; D009419:Nerve Tissue Proteins; C000715627:Nkx2-2 protein, mouse; D000071841:PAX6 Transcription Factor; D050809:POU Domain Factors; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; C084010:pancreatic and duodenal homeobox 1 protein; C074067:Pou3f4 protein, mouse; D013004:Somatostatin