LRP1 is a negative regulator of oligodendrogenesis in the adult mouse central nervous system

Oligodendrocyte progenitor cells (OPCs) are found throughout the adult central nervous system (CNS), where they continually differentiate into oligodendrocytes. This feature of OPC behaviour makes them an attractive target for remyelination enhancing therapies aimed at treating demyelinating diseases such as Multiple Sclerosis. However, for this approach to work, further information is needed about the role of specific cell-surface receptors in directing OPC behaviour in the adult CNS. One cell surface receptor that is highly expressed by OPCs, but rapidly down regulated as they differentiate into oligodendrocytes, is the low-density lipoprotein receptor related protein (LRP1). LRP1 is a member of the low-density lipoprotein receptor family, and it is capable of signalling in a variety of ways. To investigate the role that LRP1 plays in modulating adult OPCs, I conditionally deleted Lrp1 from OPCs in the healthy and demyelinated adult mouse CNS. In the healthy CNS, OPCs without Lrp1 had an increased rate of proliferation and gave rise to a larger number of newborn oligodendrocytes overtime. However, the myelinating profile of individual new oligodendrocytes was unchanged. Following cuprizone induced demyelination control mice had larger demyelinated lesions when compared to Lrp1-deleted mice, suggesting that the blockade of LRP1 signalling by OPCs could enhance remyelination. By studying the effect of Lrp1 deletion and the ligand activation of LRP1 on OPC behaviour in vitro, I determined that the effect of LRP1 on OPC proliferation was likely to be secondary to the inhibitory effect of LRP1 on OPC differentiation. These data suggest that suppressing LRP1 signalling may be useful in enhancing CNS myelin repair.