Role of Human Fractalkine Receptor Variant in Mouse Brain Development

• Author / Creator

  Bibi, Sana

• Multiple sclerosis (MS) is a degenerative disorder of the central nervous system that is triggered in genetically predisposed individuals by environmental insults. In MS, the body’s own immune cells attack and damage myelin and the myelin-producing cells, oligodendrocytes. Genetic factors contribute to both the triggers (susceptibility risk) and drivers (severity risk) of MS. Genetic variants associated with MS severity cluster into the central nervous system development category. However, to date, there are no functional studies on MS severity risk genetic variants in central nervous system development. C-X3-C motif chemokine receptor 1 (CX3CR1), a receptor for chemokine fractalkine (FKN), variants are associated with MS severity. Our lab has shown that FKN-CX3CR1 signaling is important for developmental oligodendrocyte formation. However, whether MS-associated CX3CR1 variants affect brain development and function is unknown.

  To address this knowledge gap, I analyze brains from developing and adult mice that express human MS-associated CX3CR1 (I249/M280) variant in place of the mouse CX3CR1. These mice are compared to wild type and CX3CR1 knockout (KO) mice. This study shows that in comparison to WT mice, CX3CR1 (I249/M280) variant brains display i) decreased myelin protein abundance and proportion of oligodendrocytes; ii) altered astrocytes; iii) increased activation of microglia (brain immune cells); and iv) aberrant levels of cytokines. Finally, the CX3CR1 (I249/M280) variant mice exhibit aberrant behaviour in adulthood, such as increased anxiety.

  In summary, I show that mice expressing the MS-associated human CX3CR1 variant have delayed myelination and aberrant immune environment during CNS development. These transient developmental defects may lead to aberrant brain function in adulthood. These results suggest that individuals with MS-associated variants may display aberrant brain development, which may contribute to mechanisms of neurodegeneration later in life.

• Subjects / Keywords

  • chemokine
  • oligodendrocyte
  • myelination
  • CX3CR1
  • Neurodevelopment
  • hippocampus
  • Multiple sclerosis

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-7ymx-kz79

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.