HtrA1-dependent proteolysis of TGF-ß controls both neuronal maturation and developmental survival. Homo sapiens

Transforming growth factor-ß (TGF-ß) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-ß accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice over-expressing a TGF-ß responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-ß 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-ß1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-ß 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-ß could be one of the critical events controlling both neuronal maturation and developmental survival. Keywords: HtrA1 / neuronal survival / PAI-1 / TGF-ß signalling / tPA Overall design: Total RNA were extracted from 3 cultures of 2 DIV Human neurons. For each stage, equal amounts of each RNA were pooled and 5µg were reverse-transcribed, labelled and hybridized on pangenomic microarrays. Each pool was hybridized in duplicate dye-swap independent experiments.