13349
2012
eng
e1002577
3
8
article
1
2016-05-13
--
--
Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.
PLoS Genetics
10.1371/journal.pgen.1002577
urn:nbn:de:bvb:20-opus-133490
PLoS Genetics 8(3): e1002577. doi:10.1371/journal.pgen.1002577
Xiaolin Tu
Jianquan Chen
Joohyun Lim
Courtney M. Karner
Seung-Yon Lee
Julia Heisig
Cornelia Wiese
Kameswaran Surendran
Raphael Kopan
Manfred Gessler
Fanxin Long
eng
uncontrolled
expression
eng
uncontrolled
axial skeletal defects
eng
uncontrolled
transcription factor
eng
uncontrolled
alagille syndrome
eng
uncontrolled
osteoblast differentiation
eng
uncontrolled
human jagged1
eng
uncontrolled
aortic-valve
eng
uncontrolled
T cells
eng
uncontrolled
mutations
eng
uncontrolled
mice
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13349/Tu_PLoS_2012.pdf
12403
2012
eng
379
13
article
1
2016-01-12
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Treatment-independent miRNA signature in blood of wilms tumor patients
Background
Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001.
Results
We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls.
Conclusion
Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.
BMC Genomics
10.1186/1471-2164-13-379
urn:nbn:de:bvb:20-opus-124034
BMC Genomics 2012, 13:379. doi:10.1186/1471-2164-13-379
Jana Schmitt
Christina Backes
Nasenien Nourkami-Tutdibi
Petra Leidinger
Stephanie Deutscher
Markus Beier
Manfred Gessler
Norbert Graf
Hans-Peter Lenhof
Andreas Keller
Eckart Meese
eng
uncontrolled
miRNA
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12403/Schmitt_10.1186_1471-2164-13-379.pdf
6501
2012
eng
article
1
2013-03-25
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--
Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors
HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.
urn:nbn:de:bvb:20-opus-75341
7534
In: PLoS Genetics (2012) 8: 5, doi:10.1371/journal.pgen.1002728
Julia Heisig
David Weber
Eva Englberger
Anja Winkler
Susanne Kneitz
Wing-Kin Sung
Elmar Wolf
Martin Eilers
Chia-Lin Wei
Manfred Gessler
deu
swd
Biologie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6501/026_journal.pgen.1002728.pdf