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1 Department of Cell Biology, Baylor College of Medicine,
Houston, Texas 77030 USA;
3 Division of Gastroenterology,
Digestive Disease Research Center, New England Medical Center-Tufts
University School of Medicine, Boston, Massachusetts 02111 USA
Candidate transcription factors involved in pancreatic endocrine
development have been isolated using insulin gene regulation as a
paradigm. The cell-type restricted basic helix-loop-helix (bHLH)
gene, BETA2/NeuroD, expressed in pancreatic
endocrine cells, the intestine, and the brain, activates insulin gene
transcription and can induce neurons to differentiate. To understand
the importance of BETA2 in pancreatic endocrine cell differentiation,
mice lacking a functional BETA2 gene were generated by gene
targeting experiments. Mice carrying a targeted disruption of the
BETA2 gene developed severe diabetes and died perinatally.
Homozygous BETA2 null mice had a striking reduction in the
number of insulin-producing 
cells and failed to develop mature
islets. Islet morphogenesis appeared to be arrested between E14.5 and
E17.5, a period characterized by major expansion of the cell
population. The presence of severe diabetes in these mice suggests that
proper islet structure plays an important role in blood glucose
homeostasis. In addition, secretin- and cholecystokinin-producing
enteroendocrine cells failed to develop in the absence of BETA2. The
absence of these two pancreatic secretagogs may explain the abnormal
cellular polarity and inability to secrete zymogen granules in
pancreatic acinar exocrine cells. The nervous system appeared to
develop normally, despite abundant expression of BETA2 in
differentiating neurons. Thus, BETA2 is critical for the normal
development of several specialized cell types arising from the gut
endoderm.
[Key Words: Diabetes; pancreatic endocrine development; insulin gene regulation; BETA2; NeuroD; mice; enteroendocrine development]
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