Conditional inactivation of Pax6 in the pancreas causes early onset of diabetes.
Pax6 transcription factor is required for islet cell number, morphology, and hormone gene expression. The perinatal lethality of Pax6 null mutants has restricted investigation of the role of Pax6 in normal endocrine cell function. Therefore, we devised the conditional inactivation of Pax6 using the Pdx1 and Pax6 regulatory domains to activate Cre in cells of either the entire pancreatic bud or only in endocrine cell lineages, respectively. Mutant pups died few days after birth, suffering from an overt diabetic phenotype that includes hyperglycemia, hypoinsulinemia, weight loss, and ketosis, indicating an essential role for Pax6 in beta cell function. Glucose-transporter type-2 expression was downregulated, but expression of several transcription factors essential for endocrine development was maintained. Our findings support a role for Pax6 activity in maintaining normal beta cell function after birth, but not for beta cell neogenesis during late embryonic development and early postnatal stages.
Ashery-Padan
Ruth
R
Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978 Israel. ruthash@post.tau.ac.il
Zhou
Xunlei
X
Marquardt
Till
T
Herrera
Pedro
P
Toube
Leanne
L
Berry
Asher
A
Gruss
Peter
P
D000818:Animals; D003920:Diabetes Mellitus / Q000209:etiology*; D005136:Eye Proteins; D051273:Glucose Transporter Type 2; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009474:Neurons / Q000502:physiology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010179:Pancreas / Q000502:physiology*; D011995:Recombination, Genetic; D012097:Repressor Proteins; D014157:Transcription Factors / Q000502:physiology; D029961:Zebrafish Proteins
D005136:Eye Proteins; D051273:Glucose Transporter Type 2; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009004:Monosaccharide Transport Proteins; C491328:Nkx6-1 protein, mouse; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins