Microglia in myelination
In a surprising finding, it is apparent that microglia, a type of immune cell found in the brain, make an important contribution to the formation of myelin. This project will identify how microglia interact with myelin to fine-tune structure. Understanding how microglia modulates myelin formation will open up new avenues of research into neural plasticity, which by definition has implications for learning and memory. We have recently identified that the disruption of Mertk, a key regulator of microglial behaviour, leads to abnormal myelination, including alterations in myelin thickness and decompaction.
The central aim of this project is to understand how microglia interact with myelin and the myelin-producing cells of the CNS to adapt myelin to the needs of axons, and specifically how the TAM receptor Mertk regulates this process.
This project builds upon our finding that microglia play a previously unsuspected role in the formation and remodelling of myelin; a process that is dependent upon the TAM receptor Mertk. This study will expand upon this novel finding, elucidating how microglia are involved in the remodelling of myelin. To achieve this, we will use unique genetically modified mice to examine the molecular mechanisms underpinning microglial control of myelin formation. Importantly, we will also focus upon the functional outcomes of myelin changes, providing context and relevance to our structural and molecular studies. In addition to advancing our knowledge of how the nervous system develops and functions, these studies will, in the future, be applicable for understanding the mechanisms involved in the development of diseases which involve dysmyelination (such as schizophrenia) and demyelination (such as multiple sclerosis)
Figure 1: Myelin ultrastructure is altered in the absence of Mertk in microglia, showing regions of abnormally compacted myelin.
Walsh, A., Johnson, L.J., Harvey, A.J., Kilpatrick, T.J., and Binder, M.D. (2021). Identification and characterisation of cis-regulatory elements upstream of the human receptor tyrosine kinase gene MERTK. Brain plasticity 7(1) 3-16 (2 citations)
Binder, M.D., Fox, A.D., Merlo, D., Johnson, L.J., Giuffrida, L., Calvert, S.E., Akkermann, R., Ma, G.Z.M., ANZgene, Perera, A.A., Gresle, M.M., Laverick, L., Foo, G., Fabis-Pedrini, M., Spelman, T., Jordan, M.A., Baxter, A.G., Foote, S., Butzkueven, H., Kilpatrick, T.J., Field, J. (2016) Common and low frequency variants IN MERTK are independently associated with Multiple Sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status. PLOS Genetics 12(3): e1005853