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Microphthalmia transcription factor regulates pancreatic β-cell function

Mazur, Magdalena LU ; Winkler, Marcus LU ; Ganic, Elvira LU ; Colberg, Jesper K.; Johansson, Jenny LU ; Bennet, Hedvig LU ; Fex, Malin LU ; Nuber, Ulrike LU and Artner, Isabella LU (2013) In Diabetes 62(8). p.2834-2842
Abstract
Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of... (More)
Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
MELANOMA, GENE, DIFFERENTIATION, MELANOCYTES, PAX6, GLUCOSE, MITF, EARLY-ONSET, NEURAL CREST, DIABETES-MELLITUS
in
Diabetes
volume
62
issue
8
pages
2834 - 2842
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000322431100029
  • scopus:84890872273
ISSN
1939-327X
DOI
10.2337/db12-1464
language
English
LU publication?
yes
id
449f386e-9283-4135-9597-936e2b9a007e (old id 4063576)
date added to LUP
2016-02-01 13:58:18
date last changed
2019-02-20 05:46:05
@article{449f386e-9283-4135-9597-936e2b9a007e,
  abstract     = {Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function.},
  author       = {Mazur, Magdalena and Winkler, Marcus and Ganic, Elvira and Colberg, Jesper K. and Johansson, Jenny and Bennet, Hedvig and Fex, Malin and Nuber, Ulrike and Artner, Isabella},
  issn         = {1939-327X},
  keyword      = {MELANOMA,GENE,DIFFERENTIATION,MELANOCYTES,PAX6,GLUCOSE,MITF,EARLY-ONSET,NEURAL CREST,DIABETES-MELLITUS},
  language     = {eng},
  number       = {8},
  pages        = {2834--2842},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Microphthalmia transcription factor regulates pancreatic β-cell function},
  url          = {http://dx.doi.org/10.2337/db12-1464},
  volume       = {62},
  year         = {2013},
}