Mechanisms goevrning netri-1 induced changes in oligodendroglial morphology during central nervous system development and dysfunction

Netrin-l is a bifunctional guidance cue that attracts or repels cell of the developing nervous system. Recent work has shown that netrin-l plays important roles in the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS). In the embryonic spinal cord, netrin-l repels dorsally migrating oligodendrocyte precursor cells (OPCs) by inducing a decrease in process extension. In the adult, netrin-l is expressed by mature, myelinating oligodendrocytes and is required for the maintenance ofaxo-oligodendroglial paranodal junctions. This thesis examines a role for netrin-l in oligodendrocyte maturation and during the demyelinating disorder Multiple Sclerosis (MS). I present data demonstrating that netrin-l, acting through its receptor Deleted in Colorectal Carcinoma (DCC), promotes extension and branching of oligodendrocyte processes, and induces the tonnation of myelin-like membrane sheets. These events require the activation of a signal transduction cascade involving the activation of the src-family kinase Fyn and downreb'lllation of GTPbound RhoA. I also explored a mechanism by which netrin-l ellicits contrasting morphological responses in OPCs and oligodendrocytes. Netrin-l increases RhoA activity in OPCs to induce a decrease in process length, but deactivates RhoA to induce process elaboration in oligodendrocytes. The auto immune disease Multiple Sclerosis (MS) is characterized by sporadic CNS demyelination. The last chapter of the thesis identifies the presence of netrin-l, and a proteolytic fragment of netrin-l, in MS lesions. I also detennined that netrin-l induces distinct morphological changes in humanoligodendroglia, and these changes can influence the ability of adult OPCs to efficiently remyelinate a demyelinated lesion. These results indicate that netrin-l plays distinct roles during the orphological maturation of oligodendrocytes, and continues to influence oligodendroglia in the adult CNS, a factor which has important c
La nétrine-l est une molécule de guidage axonal bifonctionnelle qui attire ou repousse les cellules nerveuses ou les axones pendant le développement du système nerveux. Des études récentes ont démontré que la nétrine-l jouc un rôle dans le développement des oligodendrocytes, les cellules productrices de myéline dans le systeme nerveux central (SNC). Dans la moelle épinière embryonnaire, la nétrine-l repousse les précurseurs d' oligodendrocytcs (OPC) dorsalement enprovoquant une réduction de croissance de leur prolongement. Chez l'adulte, la nétrine-l est exprimée par les oligodendrocytes myélinisants matures, et est requise pour le maintien des jonctions paranodales. La présente thèse étudie la fonction de la nétrine-l dans la maturation des oligodendrocytes et son rôle dans la sclérose en plaques (SP), une pathologie démyélinisante du SNC