The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity.
Brain 4 (Brn4/Pou3f4) and Pax6 are POU-homeodomain and paired-homeodomain transcription factors, respectively, that are expressed in the brain and the glucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic day 10 in the pancreas, just before pax6 and both appear in the glucagon immunoreactive cells. At a later time point, E19, no Brn4 co-localization is observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)-producing cell can be found, while Pax6 is found in all endocrine cells. These data suggest that brn4 is the only alpha-cell specific transcription factor yet identified; therefore, we sought to analyze alpha-cell development and function in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-) mice, pancreatic bud formation, glucagon cell numbers and physiological measurements all appear normal. Examination of other transcription factors found in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting that Brn4 does not regulate these transcription factors. Pax6 mutant mice (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene.
Heller
R Scott
RS
Department of Developmental Biology, Hagedorn Research Institute, DK-2820 Gentofte, Denmark. shll@hagedorn.dk
Stoffers
Doris A
DA
Liu
Aihua
A
Schedl
Andreas
A
Crenshaw
E Bryan
EB
Madsen
Ole D
OD
Serup
Palle
P
D000818:Animals; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D005934:Glucagon / Q000096:biosynthesis*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; D050809:POU Domain Factors; D051761:Paired Box Transcription Factors; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009419:Nerve Tissue Proteins; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D050809:POU Domain Factors; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; C074067:Pou3f4 protein, mouse; D005934:Glucagon