Publications (2)72.56 Total impact
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Article: ARTICLES Rfx6 directs islet formation and insulin production in mice and humans
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ABSTRACT: Insulin from the b-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 b-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 b-cells for patients with diabetes. During embryonic development, the pancreas first appears as clusters of cells on the dorsal and ventral aspects of the gut endoderm. The exocrine and endocrine cells that form the adult pancreas differenti-ate from this pool of pancreatic progenitors 1 . A single transcription factor, the pro-endocrine bHLH factor Neurog3, is both necessary and sufficient to drive these progenitor cells to differentiate into the endocrine cells that form the islets of Langerhans 2–4 . Transient activa-tion of Neurog3 expression in scattered progenitor cells initiates expression of additional transcription factors, including Neurod1, Pax4, Nkx2-2, Nkx6-1, Arx and others, which then direct the differe-ntiation of those cells into the distinct islet cell subtypes and the activation of the mature islet transcription factors such as Mafa, Pax6 and Isl1 (ref. 1). Mutations in many of these genes can cause diabetes, highlighting the pathway's importance in human b-cell formation and insulin production 5 . Understanding and controlling this process of differentiation may ultimately provide us with the cells needed to treat diabetes mellitus.Nature 01/2011; · 36.28 Impact Factor -
Article: Rfx6 directs islet formation and insulin production in mice and humans.
[show abstract] [hide abstract]
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.Nature 02/2010; 463(7282):775-80. · 36.28 Impact Factor
