Abstract
Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.
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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Basic Helix-Loop-Helix Transcription Factors / deficiency
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation*
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DNA Mutational Analysis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Diabetes Mellitus / congenital
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Diabetes Mellitus / genetics
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Diabetes Mellitus / metabolism
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Diabetes Mellitus / pathology
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Embryo, Mammalian / metabolism
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Female
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Fetus / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Developmental
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Genes, Recessive / genetics
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Genetic Testing
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Humans
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Infant, Newborn
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Insulin / biosynthesis*
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Islets of Langerhans / cytology*
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Islets of Langerhans / embryology
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Islets of Langerhans / metabolism*
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Male
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Mice
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NIH 3T3 Cells
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Organ Specificity
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Regulatory Factor X Transcription Factors
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Syndrome
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Insulin
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Nerve Tissue Proteins
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Neurog3 protein, mouse
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Regulatory Factor X Transcription Factors
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Rfx6 protein, human
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Rfx6 protein, mouse
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Transcription Factors