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Gene expression profiling of a mouse model of pancreatic islet dysmorphogenesis.

Wilding Crawford L, Tweedie Ables E, Oh YA, Boone B, Levy S, Gannon M - PLoS ONE (2008)

Bottom Line: Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized.Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals.This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated.

Methodology/principal findings: We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development.

Conclusions/significance: This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.

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Related in: MedlinePlus

Increased proliferation of glucagon+ cells in Hnf6 Tg pancreata.Proliferation rates in WT (A) versus Hnf6 Tg (B) pancreata were determined by co-immunohistochemistry for phosphorylated histone H3 (p-H3, red) and either glucagon (green) or insulin (data not shown). (C) Number of cells that co-expressed p-H3 and either glucagon or insulin are expressed as a percentage of the total hormone+ cells counted at e15.5, e18.5, and P1; **p = 0.004.
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pone-0001611-g006: Increased proliferation of glucagon+ cells in Hnf6 Tg pancreata.Proliferation rates in WT (A) versus Hnf6 Tg (B) pancreata were determined by co-immunohistochemistry for phosphorylated histone H3 (p-H3, red) and either glucagon (green) or insulin (data not shown). (C) Number of cells that co-expressed p-H3 and either glucagon or insulin are expressed as a percentage of the total hormone+ cells counted at e15.5, e18.5, and P1; **p = 0.004.

Mentions: We hypothesized that increased proliferation of glucagon+ cells could contribute in part to the increase in this cell type. As significant increases in the number of hormone+ cells can normally be detected between e14.5 and e16.5 [2], we analyzed pancreata from e15.5 embryos for co-localization of either glucagon or insulin with phosphorylated histone H3 (p-H3), a marker of mitosis, by immunofluorescence (Figure 6). Indeed, there was a significant increase in glucagon+/p-H3+ cells in Hnf6 Tg embryos as compared to WT littermates, while no difference was detected in proliferation of insulin+ cells at this time. No significant changes in proliferation could be detected in glucagon+ or insulin+ cells at e18.5 or P1 (Figure 6C).


Gene expression profiling of a mouse model of pancreatic islet dysmorphogenesis.

Wilding Crawford L, Tweedie Ables E, Oh YA, Boone B, Levy S, Gannon M - PLoS ONE (2008)

Increased proliferation of glucagon+ cells in Hnf6 Tg pancreata.Proliferation rates in WT (A) versus Hnf6 Tg (B) pancreata were determined by co-immunohistochemistry for phosphorylated histone H3 (p-H3, red) and either glucagon (green) or insulin (data not shown). (C) Number of cells that co-expressed p-H3 and either glucagon or insulin are expressed as a percentage of the total hormone+ cells counted at e15.5, e18.5, and P1; **p = 0.004.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2249940&req=5

pone-0001611-g006: Increased proliferation of glucagon+ cells in Hnf6 Tg pancreata.Proliferation rates in WT (A) versus Hnf6 Tg (B) pancreata were determined by co-immunohistochemistry for phosphorylated histone H3 (p-H3, red) and either glucagon (green) or insulin (data not shown). (C) Number of cells that co-expressed p-H3 and either glucagon or insulin are expressed as a percentage of the total hormone+ cells counted at e15.5, e18.5, and P1; **p = 0.004.
Mentions: We hypothesized that increased proliferation of glucagon+ cells could contribute in part to the increase in this cell type. As significant increases in the number of hormone+ cells can normally be detected between e14.5 and e16.5 [2], we analyzed pancreata from e15.5 embryos for co-localization of either glucagon or insulin with phosphorylated histone H3 (p-H3), a marker of mitosis, by immunofluorescence (Figure 6). Indeed, there was a significant increase in glucagon+/p-H3+ cells in Hnf6 Tg embryos as compared to WT littermates, while no difference was detected in proliferation of insulin+ cells at this time. No significant changes in proliferation could be detected in glucagon+ or insulin+ cells at e18.5 or P1 (Figure 6C).

Bottom Line: Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized.Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals.This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated.

Methodology/principal findings: We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development.

Conclusions/significance: This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.

Show MeSH
Related in: MedlinePlus