Expression of the master repressor RE-1 silencing transcription factor (REST) in beta cells leads to diabetes : 455


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Inproceedings: an article in a conference proceedings.
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Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Expression of the master repressor RE-1 silencing transcription factor (REST) in beta cells leads to diabetes : 455
Title of the conference
Minutes of the 43rd General Assembly of the European Association for the Study of Diabetes
Martin D., Caille D., Meda R., Haefliger J.A.
Amsterdam, Netherlands, September 20, 2007
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Issued date
Background and aims: The repressor RE-1 silencing transcription factor
(REST) is a master regulator of neuroendocrine genes. The generation of
transgenic mice expressing REST specifically in beta cells (RIP-REST mice)
represents a reliable system to identify the importance of REST target genes
in insulin producing cells. The observation that RIP-REST mice feature intolerance
to glucose, together with the identification of several REST target
genes that are key to exocytosis, such as Snap25 or synaptotagmin isoforms,
attested for the essential role of these genes in beta cell function. Evidences
suggest that a number of additional REST target genes are crucial for insulin
secretion, beta cell survival and overall beta cell identity.
Materials and methods: Transgenic mice were characterized by Southern
blot analyses of genomic DNA, and by immunohistochemical staining of
pancreatic sections. The secretory response of these mice was assessed by
pancreas perfusion and by measuring glycemia. Transcriptional regulation of
target genes was assessed by quantitative PCR.
Results: Glucose intolerant RIP-REST animals show a decrease in beta cell
mass, arguing that REST target genes are also involved in cell proliferation/
survival. This was further confirmed with a particular RIP-REST mice line
that display a profound hyperglycemia leading to death after few months.
This frank diabetes, observed from weaning onward, was accounted for by
a major loss of beta cell mass, as assessed by immunohistochemistry and
pancreatic insulin content measurements. The morphological analyses of
pancreas from mice at postnatal day 2 (P2), revealed a significant insulin
immunolabelling in RIP-REST diabetic mice, as compared with control animals,
suggesting that the loss of beta cells occurred after birth, and did not
arise from defects in embryonic development. In contrast, the islet morphology
in these P2 transgenic mice was strongly affected, with glucagon and
insulin positive cells scattered randomly among the islets. This phenotype,
more severe than that observed with the glucose intolerant RIP-REST mice,
is thought to be accounted for by a higher level of transgene expression. RE-1
sequence databases searches revealed a number of substantial putative target
genes, either involved in growth signal transduction pathways, or in mechanisms
of mitogenesis, that could be responsible for the observed beta cell
loss. Preliminary results point out two known regulator of cell proliferation/
survival, Ica512 and islet-brain 1, as well as an uncharacterized neuroendocrine-
specific regulatory subunit of cdk5, Cdk5r2 (p39), as bona fide REST
target genes.
Conclusion: We point out our RIP-REST mice as a pertinent model underlining
the functional importance of REST target genes in pancreatic beta
cells. Specifically, we show that the expression in beta cells of a "forbidden"
key master repressor, REST, can lead to diabetes, by a mechanism that may
rely on beta cell dysfunction, survival or differentiation. Further comprehensive
analyses of these mice will help to build up a list of essential genes of
pancreatic beta cell fate, that may play a critical role in the pathophysiology
of diabetes.
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15/10/2009 8:30
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