(Journal Article): The beta cell transcription factors and development of the pancreas.
Sander M, German M (Hormone Research Institute, University of California at San Francisco 94143-0534, USA.)
IN:
J Mol Med
1997; 75(5):327-340
ABSTRACT: The pancreatic beta cell is the major source of circulating insulin in adult mammals. In the multistep process of insulin synthesis it is initiation of transcription that restricts insulin synthesis to the beta cell since all subsequent steps can be performed by other cell types. Many of the transcription factors that bind to the insulin promoter and activate insulin gene transcription have been isolated. Some of these factors are restricted in their expression pattern, but so far no truly beta cell-specific transcriptional activator has been found. Since different transcription factors synergize to activate insulin gene transcription, cell-specific transcription of insulin is probably realized through the interactions of a unique set of regulatory proteins in the beta cell. The same transcription factors that regulate insulin gene transcription in the adult beta cell are involved in determining cell differentiation during pancreatic development. The endocrine and exocrine pancreas form from the gut endoderm as a dorsal and a ventral bud which later fuse to build a single organ. The homeodomain protein PDX-1, an insulin gene transcription factor, is uniformly expressed in the early pancreatic bud, and null mutation of PDX-1 in mice results in a failure of the pancreatic bud to grow and differentiate. Other transcription factors, such as the helix-loop-helix protein Beta-2 and the homeodomain protein Nkx 6.1, show a restricted pattern of expression during embryogenesis and in the mature islet. Those proteins may serve a dual role for the organism: during embryogenesis they may determine islet cell differentiation and in the adult they may ensure tissue-specific expression of the islet cell hormones. A better understanding of the factors involved in insulin gene transcription and islet cell differentiation will ultimately provide the basis for novel therapy of diabetes.
TYPE OF PUBLICATION: Review
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(Journal Article): PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CVE (Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175, USA.)
IN:
Development
1996; 122(3):983-995
Impact Factor(s) of Development: 7.149 (2004), 7.663 (2003), 8.624 (2001)
ABSTRACT: It has been proposed that the Xenopus homeobox gene, XlHbox8, is involved in endodermal differentiation during pancreatic and duodenal development (Wright, C.V.E., Schnegelsberg, P. and De Robertis, E.M. (1988). Development 105, 787-794). To test this hypothesis directly, gene targeting was used to make two different null mutations in the mouse XlHbox8 homolog, pdx-1. In the first, the second pdx-1 exon, including the homeobox, was replaced by a neomycin resistance cassette. In the second, a lacZ reporter was fused in-frame with the N terminus of PDX-1, replacing most of the homeodomain. Neonatal pdx-1 -/- mice are apancreatic, in confirmation of previous reports (Jonsson, J., Carlsson, L., Edlund, T. and Edlund, H. (1994). Nature 371, 606-609). However, the pancreatic buds do form in homozygous mutants, and the dorsal bud undergoes limited proliferation and outgrowth to form a small, irregularly branched, ductular tree. This outgrowth does not contain insulin or amylase-positive cells, but glucagon-expressing cells are found. The rostral duodenum shows a local absence of the normal columnar epithelial lining, villi, and Brunner's glands, which are replaced by a GLUT2-positive cuboidal epithelium resembling the bile duct lining. Just distal of the abnormal epithelium, the numbers of enteroendocrine cells in the villi are greatly reduced. The PDX-1/beta-galactosidase fusion allele is expressed in pancreatic and duodenal cells in the absence of functional PDX-1, with expression continuing into perinatal stages with similar boundaries and expression levels. These results offer additional insight into the role of pdx-1 in the determination and differentiation of the posterior foregut, particularly regarding the proliferation and differentiation of the pancreatic progenitors.
TYPE OF PUBLICATION: Original article
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