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.