Abstract
Background:
Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented.Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals.
Results:
We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone.
Conclusions:
Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Lineage* / genetics
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Eye Proteins / biosynthesis
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Eye Proteins / genetics
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Gene Expression Regulation, Developmental
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Ghrelin / biosynthesis*
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Ghrelin / genetics
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Glucagon-Secreting Cells / cytology
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Glucagon-Secreting Cells / metabolism*
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins / biosynthesis*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / metabolism*
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Islet Amyloid Polypeptide / metabolism
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / biosynthesis
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PAX6 Transcription Factor
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POU Domain Factors / biosynthesis
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Paired Box Transcription Factors / biosynthesis
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Paired Box Transcription Factors / deficiency
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism
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Repressor Proteins / biosynthesis
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Repressor Proteins / deficiency
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Repressor Proteins / genetics
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Somatostatin / biosynthesis*
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Somatostatin / genetics
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Trans-Activators / metabolism
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Transcription Factors / biosynthesis*
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Zebrafish Proteins
Substances
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ARX protein, mouse
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Eye Proteins
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Ghrelin
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins
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Islet Amyloid Polypeptide
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Nerve Tissue Proteins
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Nkx2-2 protein, mouse
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PAX6 Transcription Factor
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POU Domain Factors
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Paired Box Transcription Factors
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Pax4 protein, mouse
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Pax6 protein, mouse
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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Zebrafish Proteins
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nkx2.2b protein, zebrafish
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pancreatic and duodenal homeobox 1 protein
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Pou3f4 protein, mouse
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Somatostatin