Diabetes and pancreatic tumours in transgenic mice expressing Pa x 6.
OBJECTIVE
Both endocrine and exocrine cells of the pancreas differentiate from epithelial cells of primitive pancreatic ducts, and four types of pancreatic islet cells (alpha, beta, delta, and PP cells) are derived from the common pluripotent precursor cells. Although Pa x 6 is expressed in all islet cells, Pa x 4 is detected only in beta cells. In homozygous Pa x 4-null mice, beta cells are absent, whereas the number of alpha cells is increased. Therefore, we hypothesized that the balance of Pa x 4 and 6 is one of the determinants by which the common progenitor cells differentiate into alpha or beta cells.


METHODS
To change this balance, we generated transgenic mice overexpressing Pa x 6 driven by the insulin promoter or the PDX1 promoter.


RESULTS
In both types of transgenic mice, normal development of beta cells was disturbed, resulting in apoptosis of beta cells and diabetes. In Insulin/Pa x 6-Tg mice, beta cells were specifically affected, whereas in PDX/Pa x 6-Tg mice, developmental abnormalities involved the whole pancreas including hypoplasia of the exocrine pancreas. Furthermore, PDX/Pa x 6-Tg mice experienced proliferation of both ductal epithelia and islet cells and subsequent cystic adenoma of the pancreas.


CONCLUSIONS
These findings suggest that Pa x 6 promotes the growth of ductal epithelia and endocrine progenitor cells and that the suppression of Pa x 6 is necessary for the normal development of beta cells and the exocrine pancreas.
Yamaoka
T
T
Otsuka Department of Molecular Nutrition, School of Medicine, University of Tokushima, Japan.
Yano
M
M
Yamada
T
T
Matsushita
T
T
Moritani
M
M
Ii
S
S
Yoshimoto
K
K
Hata
J
J
Itakura
M
M
D000818:Animals; D003537:Cystadenoma / Q000235:genetics* / Q000473:pathology; D003560:Cysts / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D005136:Eye Proteins; D015870:Gene Expression; D018398:Homeodomain Proteins; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009929:Organ Size; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010179:Pancreas / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012097:Repressor Proteins
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins