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First published online June 8, 2005
doi: 10.1242/10.1242/dev.01875

Development 132, 3139-3149 (2005)
Published by The Company of Biologists 2005
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NKX6 transcription factor activity is required for {alpha}- and ß-cell development in the pancreas

Korinna D. Henseleit1,2, Shelley B. Nelson1,*, Kirsten Kuhlbrodt2,*, J. Christopher Hennings1, Johan Ericson3 and Maike Sander1,{dagger}

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

{dagger} 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 {alpha}-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 {alpha}- 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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