HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival.
Transforming growth factor-beta (TGF-beta) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-beta accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-beta-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-beta 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-beta1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-beta 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-beta could be one of the critical events controlling both neuronal maturation and developmental survival.
INSERM, INSERM U919, Serine Proteases and Pathophysiology of the neurovascular Unit (SP2U), UMR CNRS 6232 Ci-NAPs 'Center for imaging Neurosciences and Applications to Pathologies', Cyceron, University of Caen Basse-Normandie, Caen Cedex F-14074, France.
S
S
Launay
E
E
Maubert
N
N
Lebeurrier
A
A
Tennstaedt
M
M
Campioni
F
F
Docagne
C
C
Gabriel
L
L
Dauphinot
M C
MC
Potier
M
M
Ehrmann
A
A
Baldi
D
D
Vivien
D000818:Animals; D001921:Brain / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development; D002470:Cell Survival; D002478:Cells, Cultured; D000074289:High-Temperature Requirement A Serine Peptidase 1; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
D053773:Transforming Growth Factor beta1; D000074289:High-Temperature Requirement A Serine Peptidase 1; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases