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Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development
Keith R Anderson1, Peter White, Klaus H Kaestner
1Department of Biochemistry and Program in Molecular Biology, University of Colorado Health Science Center, Denver, CO 80045, USA.
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 beta cells and glucagon-expressing alpha 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.
Insights
The transcription factor Nkx2.2 is crucial for pancreatic cell development. Its absence disrupts endocrine cell differentiation and affects exocrine gene expression, revealing new regulatory roles.
Area of Science:
- Developmental biology
- Molecular endocrinology
- Gene regulation
Background:
- Nkx2.2 is a key transcription factor for pancreatic endocrine cell differentiation.
- Nkx2.2 deficiency in mice results in altered islet cell types, replacing beta and alpha cells with ghrelin-expressing cells.
- Nkx2.2 acts as both a transcriptional repressor and activator in islet formation and function.
Purpose of the Study:
- To identify genes regulated by Nkx2.2 during pancreatic endocrine and exocrine cell differentiation.
- To understand Nkx2.2's role in the developing pancreas at the onset of the secondary transition.
Main Methods:
- Gene expression profiling using microarray analysis in Nkx2.2-/- embryos at embryonic days 12.5 and 13.5.
- Assessment of differential gene expression in the absence of Nkx2.2.
Main Results:
- Identified 80 differentially expressed genes in Nkx2.2-/- embryos.
- Discovered transcription factors, signaling factors, and transmembrane proteins downstream of Nkx2.2.
- Observed misexpression of known exocrine genes in the Nkx2.2-/- pancreas.
Conclusions:
- Nkx2.2 regulates pancreas development by controlling downstream genes, including novel signaling and transmembrane proteins.
- Nkx2.2 plays a role in maintaining exocrine gene expression.
- Nkx2.2 interacts with Ngn3 in a regulatory loop critical for endocrine differentiation.
