Mechanisms of Myelination – Elucidating the Diversity of Oligodendroglial Precursors and their Local Axon-Glia Interactions

Project Information

MecMy

Grant agreement ID: 714440

DOI

10.3030/714440

Project closed

EC signature date 16 January 2017

Start date 1 February 2017

End date 31 August 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 485 000,00

EU contribution

€ 1 485 000,00

Coordinated by

THE UNIVERSITY OF EDINBURGH
United Kingdom

Periodic Reporting for period 4 - MecMy (Mechanisms of Myelination – Elucidating the Diversity of Oligodendroglial Precursors and their Local Axon-Glia Interactions)

Reporting period: 2021-08-01 to 2022-08-31

Summary of the context and overall objectives of the project

Nervous system function requires precise communication between myriads of nerve cells and surrounding glial cells to form and maintain a functional organ.

Most connections between nerve cells (axons) are eventually surrounded with myelin, an insulating structure produced by specialized glia called oligodendrocytes. This cellular interaction enables fast signal transmission, ensures long-term axon survival, and is involved in regulating learning and memory formation.
The formation of new myelin during lifelong development and after myelin damage requires differentiation of oligodendrocyte precursors. Although these cells are an abundant population in our brains lifelong, myelin repair is often inefficient and eventually fails. It is known that oligodendroglial precursors have diverse properties, but whether this diversity is at any level a regulatory factor for normal myelination, or causal to failure of myelin repair is unclear.

In this action, we elucidate the diversity of oligodendrocyte precursors by carrying out a clonal analysis of oligodendrocyte properties and fates in order to address if all oligodendrocyte are equally capable to contribute to myelin formation, and to investigate how these cells might differ.
To achieve these goals we use zebrafish, an ideally suited model organism for in vivo live cell imaging and genetic manipulation. We carry out a clonal analysis of oligodendrocyte precursor population dynamics during myelinated tract formation. We analyse the molecular signature of cells with different properties, profile their physiology and their cell fate responses to external manipulation.

This work will provide fundamentally new insights into the principles of the heterogeneity of oligodendroglial precursors and may help to device new strategies of how to employ these cells to form new myelin in development and disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

With the start of this project, we have generated a set of novel and unique reagents and assays with which to monitor the diversity of oligodendrocyte properties at unprecedented resolution over time. To achieve this, we took advantage of the properties that the zebrafish model system offers to carry out highly efficient genetic and transcriptomic analysis, in combination with high-resolution imaging approaches to carry out a systems-wide interrogation of oligodendrocyte diversity and fates in real time. Using these reagents and assays, this project has provided two chief results. First, we could identify that oligodendrocyte precursors are not a homogenous population of cells, but that subgroups of this cell type exist with different propensities and abilities to contribute to the myelination. Second, we have identified an entirely novel function for oligodendrocyte precursor cells that is independent of their traditional roles in generating myelinating cells. We discovered that non-myelinating oligodendrocyte precursors sculpt neural circuit organisation through fine-tuning of axon arborisation. Together, these results have thus led to the identification of functionally distinct subgroups of oligodendrocyte precursor cells with differential functions, which we have disseminated in publications in leading-international journals and by oral communication to expert and wider audiences over the course of this project. Our results now help understand and device strategies how to harness the capacities of this glial cell type in nervous system development, plasticity, and repair.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Until the beginning of this project, it was generally believed that oligodendrocyte precursor cells are the relatively homogenous population of cells in the central nervous system, whose only function is the generation of myelinating oligodendrocytes. The main scientific advance of his project has been that this traditional view needs to be completely overhauled. We could reveal that oligodendrocyte precursors are not homogenous but that they are instead heterogenous cells with diverse properties. Furthermore, we could reveal that the generation of myelinating oligodendrocytes is not the only function this cell type, but instead that oligodendrocyte precursors have mature myelination-independent functions through the regulation of axon remodelling and neural circuit formation. These discoveries have major implications for future studies. First, it will help identify and target subpopulations of oligodendrocytes more precisely in order to obtain more efficient myelin regeneration of the central nervous system, which is an often-proposed strategy to improve functional recovery when myelin is lost or damaged. Second, the identification of myelination-independent functions for oligodendrocyte precursors by regulation of circuit connectivity opens an entirely new area of future research, begging to now address the role of this cell type in neurodevelopmental disorders of circuit connectivity, ranging for autism spectrum disorders to learning disabilities.

Image of a larval zebrafish with fluorescently labelled oligodendrocyte precursor cells its brain