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| Status |
Public on Jul 31, 2015 |
| Title |
Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Aims/hypothesis Pancreatic beta cells maintain glucose
homeostasis and beta cell dysfunction is a major risk factor
in developing diabetes. Therefore, understanding the developmental
regulatory networks that define a fully functional beta
cell is important for elucidating the genetic origins of the disease.
Aldehyde dehydrogenase activity has been associated
with stem/progenitor cells and we have previously shown that
Aldh1b1 is specifically expressed in pancreas progenitor
pools. Here we address the hypothesis that Aldh1b1 may regulate
the timing of the appearance and eventual functionality
of beta cells.
Methods We generated an Aldh1b1-knockout mouse line
(Aldh1b1tm1lacZ) and used this to study pancreatic development,
beta cell functionality and glucose homeostasis in the
absence of Aldh1b1 function.
Results Differentiation in the developing pancreas of
Aldh1b1tm1lacZ null mice was accelerated. Transcriptome
analyses of newborn and adult islets showed misregulation of
key beta cell transcription factors and genes crucial for beta cell
function. Functional analyses showed that glucose-stimulated
insulin secretion was severely compromised in islets isolated
from null mice. Several key features of beta cell functionality
were affected, including control of oxidative stress, glucose
sensing, stimulus-coupling secretion and secretory granule
biogenesis. As a result of beta cell dysfunction, homozygous
mice developed glucose intolerance and age-dependent
hyperglycaemia.
Conclusions/interpretation These findings show that
Aldh1b1 influences the timing of the transition from the pancreas
endocrine progenitor to the committed beta cell and
demonstrate that changes in the timing of this transition lead
to beta cell dysfunction and thus constitute a diabetes risk
factor later in life.
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| |
|
| Overall design |
Islets were isolated from postnatal day one and 8 week old Aldh1b1 null and wt mice. For each P1 samples islets from three mice were combined. Each week 8 sample came from a single mouse. Three samples were analysed per genotype and time point
|
| Web link |
http://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/pubmed/?term=anastasiou+gavalas
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| |
|
| Contributor(s) |
Anastasiou V, Ninou E, Alexopoulou D, Stertmann J, Müller A, Dahl A, Solimena M, Speier S, Serafimidis I, Gavalas A |
| Citation(s) |
26518685 |
| Submission date |
May 28, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Anthony Gavalas |
| Organization name |
TU Dresden
|
| Street address |
Fetscherstr. 105
|
| City |
Dresden |
| ZIP/Postal code |
01307 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA248729 |
| SRA |
SRP042335 |
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