Thèse de doctorat en Neurosciences
Sous la direction de Anne Baron-Van Evercooren.
Soutenue en 2007
à Paris 6 .
We have demonstrated by RT-PCR, immunohistochemistry and ELISA that BMP-7 and its receptors are present in histologically normal human crypts, in aberrant crypt foci in sigmoiditis, in human colorectal tumors and in several colorectal cancer cell lines. We have also demonstrated that BMP-7 is a scatter and invasion factor. This invasive capacity of BMP-7 is independent of SMAD4 and src activity, but is associated to the cyclic activation of RhoGTPases (Rac1 and RhoA), to FAK activation (tyr925 phosphorylation associated with angiogenesis and invasion) and to MAPK/SAPK activation (JNK and ERK1/2). Taken together my PhD work strongly suggests that BMP-7 acts as dissemination and a proinvasive factor via an autocrine and paracrine mechanism. This cytokine has divergent roles on human colon cancer progression. A beneficial role, by opposing itself to inflammation and a pejorative role by helping cancer progression on the latest stages associated to invasive capacity and to adenoma-carcinoma transition
Toward the understanding of molecular and pathophysiological mechanisms leading to neuromuscular hyperactivity in Schwartz-Jampel syndrome
Pas de résumé disponible.
Schwartz-Jampel syndrome (SJS) is an autosomal recessive human disease, characterized by muscle stiffness and chondrodysplasia and caused by mutations in the perlecan gene. During my PhD, we identified 22 new SJS mutations. Molecular analyzes (mRNA and protein) showed an hypomorph effect of these mutations, allowing the production of a residual amount of functional perlecan. In order to understand the pathophysiological mechanism leading to SJS, we generated a mouse model by inserting the SJS missense p. C1532Y mutation. Homozygous mutants are viable and fertile but show locomotor defects and neuromuscular hyperactivity. Cellular defects in skeletal muscles are suggestive of denervation-reinnervation processes. Neuromuscular junctions are remodelled with a lack of the typical pretzel-like shape, acetylcholinesterase (AChE) deficiency and partial denervation. Electrophysiological analyzes reveal functional consequences of AChE deficiency but not sufficient to lead to synaptic hyperactivity and an additional effect of presynaptic abnormalities is thus suggested.