Abstract
Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.
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Abbreviations
- 4-OHT:
-
4-hydroxytamoxifen
- ActCasp3:
-
active caspase 3
- CNS:
-
central nervous system
- CP:
-
cortical plate
- CTB:
-
cholera toxin B
- DSB:
-
double-stranded breaks
- ER:
-
endoplasmic reticulum
- FT:
-
fusion of two telomers
- MEFs:
-
mouse embryonic fibroblasts
- MN:
-
micronuclei
- NPB:
-
nucleoplasmic bridge
- NSCs:
-
neural stem cells
- PC:
-
Purkinje cells
- pH3:
-
phospho-histone-3
- SCF:
-
sister chromatid fusion
- SNARES:
-
soluble N-ethylmaleimidine-sensitive factor attachment protein receptors
- SVZ:
-
sub–ventricular zone
- TGN:
-
trans-Golgi network
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
- VZ:
-
ventricular zone
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Acknowledgements
We thank the DKFZ animal facility for excellent husbandry. We also thank Alexander Ernst and Lukas Leib for great technical assistance as well as Lionel Larribere and Johannes Ridinger for their advices on qPCR experiments. This work was supported by the Deutsche Forschungsgemeinschaft (DFG): FR 2704/1-1 to POF ‘Emmy Noether program’.
Author contributions
PG performed all the experiments for the characterization of Rint1-deficient mouse. CH and PJM contributed to the creation of the Rint1 conditional mouse. AvD provided histology and pathology expertise. PJM and AvD contributed also to the final version of the manuscript. POF was project leader and produced the final version of the manuscript.
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Grigaravicius, P., Kaminska, E., Hübner, C. et al. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ 23, 454–468 (2016). https://doi.org/10.1038/cdd.2015.113
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DOI: https://doi.org/10.1038/cdd.2015.113
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