Abstract
Transforming growth factor-β (TGF-β) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-β accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-β-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-β signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-β1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-β signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-β could be one of the critical events controlling both neuronal maturation and developmental survival.
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Accession codes
Abbreviations
- HtrA:
-
high temperature responsive antigen
References
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Acknowledgements
We thank Pr Tony Wyss Coray for providing us the SBE-Luc transgenic mice, Benoit Roussel for his help in microarray data submission and Dr Carine Ali for her scientific assistance. We are grateful to Novartis for the generous gift of HtrA1 inhibitor: NVP-LBG976. This work was supported by a CIFRE grant from ANRT (National Association for Technical Research) and from Cellial Technologies.
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Launay, S., Maubert, E., Lebeurrier, N. et al. HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival. Cell Death Differ 15, 1408–1416 (2008). https://doi.org/10.1038/cdd.2008.82
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DOI: https://doi.org/10.1038/cdd.2008.82
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