Mertk and the regulation of neural precursor cells
In multiple sclerosis (MS) the protective sheath around nerves, known as myelin, is damaged and lost. This loss disrupts electrical impulses and exposes nerves to immune attack, leading to their death. Current MS therapies suppress the immune response but do not promote repair or prevent disease progression.
Following the loss of myelin, the brain has a normal process to repair myelin and restore nerve function, although in MS, this process is limited and eventually fails. One particular problem with the natural process is that the myelin that is produced is thinner than normal.
The recent discovery that stem cells in the brain not only contribute to myelin repair, but also make myelin of normal thickness, offer the potential to enhance the brain's normal repair process. However, the mechanism underlying this process is not well understood.
The goal of this project is to examine the role of a protein known as Mertk, which is expressed by stem cells in the brain, in controlling the response of these cells to myelin injury.
We aim to establish the contribution of Mertk to SVZ neural precursor cell proliferation and differentiation under normal conditions and following induction of demyelination
In the mammalian brain, neural cells are produced throughout adult life. These newly born cells are derived from neural precursor cells (NPCs), which are found in two neurogenic niches - the subgranular zone (SGZ), and the subventricular zone (SVZ). Following demyelination, NPCs derived from the SVZ contribute significantly to the production of myelinating oligodendrocytes, which produce myelin that is structurally equivalent to normal undamaged myelin. NPCs are therefore an attractive target for development of therapeutics directed towards myelin repair. However, little is known about the mechanisms that control the response of these cells to myelin damage.
NPCs are known to express a cell surface receptor known as Mertk, which we have previously identified as an MS-risk gene. Deletion of both Mertk and its sister receptor Axl results in early differentiation of neurons derived from the SVZ, suggesting (albeit indirectly) that signalling via these receptors is important for maintenance of the NPC population. Importantly, these results were not replicated in mice in which only Axl was deleted, suggesting that Mertk is the receptor involved in the maintenance of NPCs. Recent work has identified that loss of Pros1, a ligand for Mertk (but not Axl), results in altered proliferation and differentiation of neural stem cells from the SVZ.
These data strongly suggest that Mertk is critical for the maintenance of NPCs within the SVZ, an hypothesis that will be explicitly tested in this project. In addition, we will examine the role of Mertk upon NPC differentiation during myelin repair following demyelination.
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