Functional heterogeneity of oligodendrocyte progenitor cells in the central nervous system

Oligodendrocytes are the myelinating cells of the central nervous system (CNS), whose function is to optimise neuronal transmission and preserving axonal integrity. Oligodendrocytes are derived from a stem cell population, called oligodendrocyte progenitor cells (OPCs). Oligodendrocyte lineage cells (OLCs) have been implicated in the pathophysiology of various diseases including not only demyelinating diseases (eg. Multiple Sclerosis (MS) or Pelizaeus-Merzbacher disease (PMD)), but also psychiatric disorders (eg. schizophrenia or Rett syndrome (RTT)). Regardless of the type of disease, understanding the underlying fundamental biology of the oligodendrocyte lineage cells is pivotal to develop therapeutic strategies. In the mouse embryonic forebrain OPCs are generated in consecutive waves from distinct brain regions along a spatiotemporal gradient; with ventral OPCs emerging before dorsal OPCs. The developmentally distinct OPCs, and their progenies, persist in the brain throughout life. To investigate whether ventrally and dorsally derived OLCs fulfil different functions in the adult brain, dorsally derived OPCs were ablated in development using a \textit{Sox10}-driven diphtheria toxin fragment A (DTA) mouse model. As dorsally derived OPCs populate the cortex, locomotor coordination and cognition were investigated following dorsal OPC ablation. Mice ablated of the dorsal OPC population do not show a significant deficit in learning and attentional function. In contrast, ablated mice show an impaired locomotor coordination, while general vigilance, gait, balance and sensation are comparable to control groups. The locomotor coordination disabilities are a result of alterations of brain, not spinal cord homeostasis, as only a neglect able number of OLCs in the spinal cord are affected by the ablation model. In addition, no signs of neuronal cell death or chronic inflammatory response was detected in response to the ablation. As the oligodendrocyte numbers are similar between control and ablated animals, the locomotor coordination phenotype can also not be explained by reduced number of oligodendrocytes. However, clustering analysis following single-cell Drop-sequencing uncovered a heterogeneity of oligodendrocyte (OL) subpopulations in the motor cortex. Whilst some OL subpopulations are of mixed developmental origin, others are exclusively formed by either ventrally or dorsally derived OLs, arguing that dorsal oligodendrocyte subpopulations are crucial for homeostatic brain function. In the absence of dorsal OPCs, ventral OPCs are not capable of forming dorsal oligodendrocyte subpopulations in response to dorsal OPC ablation. In conclusion, my results indicate a functional heterogeneity of developmentally-distinct oligodendrocytes in physiological brain function.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2018

Author dc:creator

• Förster, Sarah

Advisor dc:contributor.advisor

• Franklin, Robin JM

• Stem cells
• Heterogeneity
• Oligodendrocyte
• Myelin
• Development

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/bea8ec09-ca99-4a16-ab4a-ce2e373debdd/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

Author Identifier

0000-0002-2585-0621

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/275822