To define when and where the oligodendrocyte lineage emerges during development.
To elucidate the induction and molecular mechanisms which are responsible for the specification of this lineage.
To make available experimental systems that will permit the screening of factors that induce a mobilization of oligodendrocyte precursors to repair demyelinating lesions.
The rationale for our project stems from the observation that in Multiple Sclerosis, although in recent plaques there are attempts at remyelination, this endogenous repair process is insufficient, during the course of the disease. Therefore, it is important to increase the number of remyelinating oligodendrocytes in the vicinity of lesions by inducing or increasing the number of oligodendrocyte progenitors to migrate out from the zone where they are produced towards the plaques. These cells can then differentiate into myelinating oligodendrocytes. To reach this goal, major gaps in our present knowledge concerning the origin of oligodendrocytes await clarification. We also need to reveal the molecular events that drive stem cells or multipotential cells of the neuroepithelium in the neural tube to differentiate into oligodendrocytes. Assuming that during neural regeneration there is a recapitulation of the molecular and cellular events that take place during development, we have chosen to study the emergence of the oligodendrocyte lineage during embryonic development.
To solve this question we felt absolutely vital to gather a panel of scientists i) having a common interest in the field of glial cells ii) covering a large scope of complementary domains of technical expertise, including experimental embryologists, cellular and molecular biologists, and iii) able to tackle the problem on different animal models: Drosophila, chicken and mouse.
1) The regional potentialities of the CNS to generate oligodendrocytes will be analysed using homotypic and isochronic transplantations of quail embryo neural tube portions sampled along the rostro-caudal and ventro-dorsal axis, into chick embryos.
2) The putative commitment of these neural tube territories towards the oligodendroglial lineages will be analysed both in vitro and in vivo (heterotopic and heterochronic transplantations).
3) The induction of the oligodendroglial lineage will be studied both in vitro and in vivo by examining the effects of the notochord, the foor plate and a series of candidate factors.
4) Mouse transcription factors and specific proteins that mark the commitment of neuroepithelial cells towards the oligodendrocyte lineage will be identifyed, and genes specifying the glial cell lineage, in Drosophila, isolated.
5) Transgenic mice bearing a tag to purify oligodendrocyte precursors will be generated.
Funding SchemeCSC - Cost-sharing contracts
EH8 9YL Edinburgh