Abstract
Pancreatic development depends on the transcription factor Pax6, which controls islet cell differentiation and hormone production. To understand the regulation of Pax6 pancreatic expression, we have identified a minimal Pax6 pancreatic enhancer and show that it contains a composite binding site for Meis and Pbx homeoproteins. We further show that Meis proteins are expressed during pancreatic development, and together with Pbx, are able to form a synergistic binding complex on the Pax6 pancreatic enhancer. When tested in transgenic mice, both the Meis and Pbx sites are essential for Pax6 pancreatic enhancer activity, and the composite site can be functionally replaced by a consensus Meis-Pbx sequence. In addition, analysis of Pbx1 and Pbx2 knockout mice demonstrates that, during pancreatic islet formation, Pax6 expression becomes dependent upon Pbx1 and Pbx2 function. As Meis homeoproteins have been previously demonstrated to regulate Pax6 expression during lens development, these results suggest a conserved mechanism of Pax6 regulation by Meis homeoproteins in two different organs.
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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Binding Sites
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Down-Regulation / genetics
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Enhancer Elements, Genetic
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Eye Proteins / antagonists & inhibitors
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Eye Proteins / genetics
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Eye Proteins / metabolism*
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Homeodomain Proteins / physiology*
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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PAX6 Transcription Factor
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Paired Box Transcription Factors / antagonists & inhibitors
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism*
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Pancreas / embryology*
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Pancreas / metabolism
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Pre-B-Cell Leukemia Transcription Factor 1
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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Eye Proteins
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Homeodomain Proteins
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PAX6 Transcription Factor
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PAX6 protein, human
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Paired Box Transcription Factors
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Pax6 protein, mouse
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Pbx1 protein, mouse
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Pbx2 protein, mouse
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Pre-B-Cell Leukemia Transcription Factor 1
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Proto-Oncogene Proteins
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Repressor Proteins
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Transcription Factors