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Open Access Highly Accessed Research article

Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development

Keith R Anderson1, Peter White34, Klaus H Kaestner3 and Lori Sussel12*

Author Affiliations

1 Department of Biochemistry and Program in Molecular Biology, University of Colorado Health Science Center, Denver, CO, 80045, USA

2 Department of Genetics and Development, Columbia University, New York, NY 10032, USA

3 Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, 752B CRB, 415 Curie Blvd, Philadelphia, Pennsylvania 19104, USA

4 The Research Institute at Nationwide Children's Hospital, 700 Childrens Drive, Columbus, OH 43205, USA

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BMC Developmental Biology 2009, 9:65  doi:10.1186/1471-213X-9-65

Published: 10 December 2009

Abstract

Background

The homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin-expressing cells. Additional studies have suggested that Nkx2.2 functions both as a transcriptional repressor and activator to regulate islet cell formation and function. To identify genes that are potentially regulated by Nkx2.2 during the major wave of endocrine and exocrine cell differentiation, we assessed gene expression changes that occur in the absence of Nkx2.2 at the onset of the secondary transition in the developing pancreas.

Results

Microarray analysis identified 80 genes that were differentially expressed in e12.5 and/or e13.5 Nkx2.2-/- embryos. Some of these genes encode transcription factors that have been previously identified in the pancreas, clarifying the position of Nkx2.2 within the islet transcriptional regulatory pathway. We also identified signaling factors and transmembrane proteins that function downstream of Nkx2.2, including several that have not previously been described in the pancreas. Interestingly, a number of known exocrine genes are also misexpressed in the Nkx2.2-/- pancreas.

Conclusions

Expression profiling of Nkx2.2-/- mice during embryogenesis has allowed us to identify known and novel pancreatic genes that function downstream of Nkx2.2 to regulate pancreas development. Several of the newly identified signaling factors and transmembrane proteins may function to influence islet cell fate decisions. These studies have also revealed a novel function for Nkx2.2 in maintaining appropriate exocrine gene expression. Most importantly, Nkx2.2 appears to function within a complex regulatory loop with Ngn3 at a key endocrine differentiation step.