Rfx6 directs islet formation and insulin production in mice and humans

• Published in: Nature (London) Vol. 463; no. 7282; pp. 775 - 780
• Main Authors: Polychronakos, Constantin, German, Michael S, Smith, Stuart B, Qu, Hui-Qi, Taleb, Nadine, Kishimoto, Nina Y, Scheel, David W, Lu, Yang, Patch, Ann-Marie, Grabs, Rosemary, Wang, Juehu, Lynn, Francis C, Miyatsuka, Takeshi, Mitchell, John, Seerke, Rina, Désir, Julie, Eijnden, Serge Vanden, Abramowicz, Marc, Kacet, Nadine, Weill, Jacques, Renard, Marie-Ève, Gentile, Mattia, Hansen, Inger, Dewar, Ken, Hattersley, Andrew T, Wang, Rennian, Wilson, Maria E, Johnson, Jeffrey D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2010; Nature Publishing Group
• Subjects: 631/136/142; 631/443/319/1642/137; 631/45/612/822; 692/698/1460/1583; Animals; Artificial chromosomes; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding proteins; Biological and medical sciences; Care and treatment; Causes of; Cell Differentiation; Diabetes; Diabetes Mellitus - congenital; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Diabetes. Impaired glucose tolerance; DNA Mutational Analysis; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryo, Mammalian - metabolism; Embryonic development; Embryonic growth stage; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fetus - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes, Recessive - genetics; Genetic aspects; Genetic Testing; Human subjects; Humanities and Social Sciences; Humans; Infant, Newborn; Insulin; Insulin - biosynthesis; Islets of Langerhans - cytology; Islets of Langerhans - embryology; Islets of Langerhans - metabolism; Male; Medical sciences; Mice; multidisciplinary; Mutation; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NIH 3T3 Cells; Organ Specificity; Proteins; Regulatory Factor X Transcription Factors; Science; Science (multidisciplinary); Stem cells; Syndrome; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; United States; Endocrinopathy; Human; Embryonic development; Diabetes mellitus; Langerhans islet; Rodentia; Vertebrata; Mammalia; Gene; Mouse; Animal; β Cell; Differentiation; Transcription factor; Endocrine pancreas
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08748

Insulin from the β-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 β-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 β-cells for patients with diabetes. Insulin production boosted by Rfx6 The transcription factor neurogenin 3 (Neurog3) initiates the differentiation of insulin-producing β-cells and other islet cell types from pancreatic endoderm in the developing embryo, but the genetic program that subsequently completes this differentiation is incompletely understood. German et al . now show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Loss of Rfx6 function in mice leads to specific loss of pancreatic-polypeptide-producing cells, while in human infants mutations in RFX6 underlie a recessive syndrome of neonatal diabetes. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors coordinating pancreatic islet development. Rfx6 could prove useful in efforts to generate β-cells for patients with diabetes. Pancreatic β-cells release insulin, which controls energy homeostasis in vertebrates, and its lack causes diabetes mellitus. The transcription factor neurogenin 3 (Neurog3) initiates differentiation of β-cells and other islet cell types from pancreatic endoderm; here, the transcription factor Rfx6 is shown to direct islet cell differentiation downstream of Neurog3 in mice and humans. This may be useful in efforts to generate β-cells for patients with diabetes.