Rfx6 directs islet formation and insulin production in mice and humans.
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.
Smith
Stuart B
SB
Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA.
Qu
Hui-Qi
HQ
Taleb
Nadine
N
Kishimoto
Nina Y
NY
Scheel
David W
DW
Lu
Yang
Y
Patch
Ann-Marie
AM
Grabs
Rosemary
R
Wang
Juehu
J
Lynn
Francis C
FC
Miyatsuka
Takeshi
T
Mitchell
John
J
Seerke
Rina
R
Désir
Julie
J
Vanden Eijnden
Serge
S
Abramowicz
Marc
M
Kacet
Nadine
N
Weill
Jacques
J
Renard
Marie-Eve
ME
Gentile
Mattia
M
Hansen
Inger
I
Dewar
Ken
K
Hattersley
Andrew T
AT
Wang
Rennian
R
Wilson
Maria E
ME
Johnson
Jeffrey D
JD
Polychronakos
Constantin
C
German
Michael S
MS
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000151:congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000096:biosynthesis*; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D000071701:Regulatory Factor X Transcription Factors; D013577:Syndrome; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C407737:Neurog3 protein, mouse; C547964:Rfx6 protein, human; C547963:Rfx6 protein, mouse