NKX6 transcription factor activity is required for α- andβ-cell development in the pancreas
Author:
Henseleit Korinna D.12, Nelson Shelley B.1, Kuhlbrodt Kirsten2, Hennings J. Christopher1, Ericson Johan3, Sander Maike1
Affiliation:
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
Abstract
In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting β-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 β-cell formation. From these studies, the homeodomain transcription factor NKX6.1 has proven to be a key player. In Nkx6.1 mutants, β-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 residualβ-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 α-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 regulateα- as well as β-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.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference37 articles.
1. Apelqvist, A., Li, H., Sommer, L., Beatus, P., Anderson, D. J.,Honjo, T., Hrabe de Angelis, M., Lendahl, U. and Edlund, H.(1999). Notch signalling controls pancreatic cell differentiation. Nature400,877-881. 2. Awatramani, R., Beesley, J., Yang, H., Jiang, H., Cambi, F.,Grinspan, J., Garbern, J. and Kamholz, J. (2000). Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity. J. Neurosci. Res.61,376-387. 3. Bellefroid, E. J., Bourguignon, C., Hollemann, T., Ma, Q.,Anderson, D. J., Kintner, C. and Pieler, T. (1996). X-MyT1, a Xenopus C2HC-type zinc finger protein with a regulatory function in neuronal differentiation. Cell87,1191-1202. 4. Dor, Y., Brown, J., Martinez, O. I. and Melton, D. A.(2004). Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature429,41-46. 5. Gradwohl, G., Fode, C. and Guillemot, F.(1996). Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors. Dev. Biol.180,227-241.
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