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First published online June 8, 2005
doi: 10.1242/10.1242/dev.01875
- and ß-cell development in the pancreas
1 Department of Developmental and Cell Biology, University of California at
Irvine, 4203 McGaugh Hall, Irvine, CA 92697-2300, USA
2 Center for Molecular Neurobiology, Martinistrasse 85, 20251 Hamburg,
Germany
3 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska
Institute, S-171 77 Stockholm, Sweden
Author for correspondence (e-mail:
msander{at}uci.edu)
Accepted 21 April 2005
In diabetic individuals, the imbalance in glucose homeostasis is caused by
loss or dysfunction of insulin-secreting ß-cells of the pancreatic
islets. As successful generation of insulin-producing cells in vitro could
constitute a cure for diabetes, recent studies have explored the molecular
program that underlies ß-cell formation. From these studies, the
homeodomain transcription factor NKX6.1 has proven to be a key player. In
Nkx6.1 mutants, ß-cell numbers are selectively reduced, while
other islet cell types develop normally. However, the molecular events
downstream of NKX6.1, as well as the molecular pathways that ensure residual
ß-cell formation in the absence of NKX6.1 are largely unknown. Here, we
show that the Nkx6.1 paralog, Nkx6.2, is expressed during
pancreas development and partially compensates for NKX6.1 function.
Surprisingly, our analysis of Nkx6 compound mutant mice revealed a
previously unrecognized requirement for NKX6 activity in 
-cell
formation. This finding suggests a more general role for NKX6 factors in
endocrine cell differentiation than formerly suggested. Similar to NKX6
factors, the transcription factor MYT1 has recently been shown to regulate
- as well as ß-cell development. We demonstrate that expression of
Myt1 depends on overall Nkx6 gene dose, and therefore identify
Myt1 as a possible downstream target of Nkx6 genes in the endocrine
differentiation pathway.
Key words: Nkx6.1, Nkx6.2, Myt1, Pancreas, Islet, Endocrine, Insulin, Glucagon, Development, Mouse
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