Periodic Reporting for period 3 - MecMy (Mechanisms of Myelination – Elucidating the Diversity of Oligodendroglial Precursors and their Local Axon-Glia Interactions)
Reporting period: 2020-04-01 to 2021-07-31
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.
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.
Up to this stage, we have generated a set of novel and unique reagents and assays with which to monitor oligodendrocyte properties at unprecedented resolution over time. We have used these reagents to profile oligodendrocyte properties and fates using intravital microscopy to determine intercellular relationships.
We have isolated oligodendrocytes and assessed their gene expression profile using RNA sequencing and we have mapped developmental fates of cells with distinct molecular profiles. Together, this work so far has led to the identification of functionally distinct subgroups of oligodendrocyte precursor cells with differential functions.
We have isolated oligodendrocytes and assessed their gene expression profile using RNA sequencing and we have mapped developmental fates of cells with distinct molecular profiles. Together, this work so far has led to the identification of functionally distinct subgroups of oligodendrocyte precursor cells with differential functions.
The major scientific advance of this project is that we could identify that not all oligodendrocyte are equally capable of contributing to the formation of new myelin.
Expected results until the end of the project: First, we aim to identify how oligodendrocyte may be manipulated by physiological stimuli of surrounding cells to differentiate to produce myelin. Second, we aim to start investigate which role non-differentiated oligodendrocytes might play for nervous system function, if it is not the formation of new myelin.
Expected results until the end of the project: First, we aim to identify how oligodendrocyte may be manipulated by physiological stimuli of surrounding cells to differentiate to produce myelin. Second, we aim to start investigate which role non-differentiated oligodendrocytes might play for nervous system function, if it is not the formation of new myelin.