How does oligodendrocyte transcriptional heterogeneity change biological function?

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Oligodendrocytes, first described 100 years ago, are cells in the brain and the spinal cord that form myelin sheaths around nerves. Myelin sheaths act like the insulation on wires, protecting and speeding up the conduction of electrical impulses along nerves. Oligodendrocytes also feed the underlying nerves by passing metabolites though the myelin sheath to the nerve, sustaining it. These cells are very important to the function of the brain and spinal cord, and formation of myelin is essential for development, learning (even in adulthood) and the decline in the myelin structure is associated with normal ageing.Although all oligodendrocytes broadly show these functions, we now know that they are actually not all the same. Recent technology shows that the genes that are active in oligodendrocytes vary if they come from the brain compared to the spinal cord, but there are even differences between oligodendrocytes within the same areas of the brain and spinal cord and these differences change with ageing. These different patterns of gene activity suggest that the functions of these oligodendrocyte subtypes also vary, leading to the prediction that some may be better at making myelin and some better at providing nutritional support. These oligodendrocyte subtypes vary between different species of animals, with some only existing in humans, suggesting that some aspects of oligodendrocyte function may be human-specific. We also do not know whether these oligodendrocyte subtypes are static or whether the subtype and pattern of gene activity in a cell can change as needed to alter function. To find out how different human oligodendrocytes work, we must test these predictions of different function biologically in the laboratory.This project will test these predictions in human oligodendrocytes that we will generate in the dish from stem cells (embryonic stem cells) making both brain and spinal cord subtype patterns. We will first make genetic tools tagging the different subtypes of oligodendrocytes with fluorescent colours. We can then grow these in the dish (in 2 or 3-dimensions) and after transplanted into the mouse, to find out how brain and spinal cord oligodendrocytes are different, how different subtypes are generated, and whether they can change. We will discover which genes need to be activated to generate the different subtypes of oligodendrocytes and use these to make more of the different subtypes. We will then test the ability of each type to make myelin and provide nutritional support in our cultures and in the mouse.This will give us an understanding of the fundamental differences between human oligodendrocyte subtype in making myelin and providing nutritional support to nerves.