Pericyte deficiencies in a foxf2 loss of function mutant

Pericytes are critical players in vascular development and disease but are not widely studied in the context of cerebral small vessel disease, a vascular condition related to stroke that progressively weakens brain microvessels. Foxf2, a pericyte-expressed gene, is involved in vascular stability and reduced FOXF2 is associated with increased stroke risk and CSVD prevalence. Here, I use a zebrafish foxf2a loss of function mutant as a genetic model of CSVD to show pathological alterations in brain pericytes. Not only are there fewer brain pericytes across the lifespan, but these pericytes also exhibit morphological abnormalities like increased soma size, process length and degeneration. These abnormalities manifest differently in adult brains, and blood vessel defects are evident. I show that embryonic pericyte defects are not the result of decreased pericyte density but a combination of cell-autonomous and non-cell-autonomous effects. A downstream target of foxf2a, loxl2b, is downregulated in foxf2 mutants. While loxl2b mRNA is sufficient to boost brain pericyte numbers, mutants for this gene do not show an obvious phenotype, suggesting a more complicated role. This thesis sheds light on novel lifespan defects in mutant brain pericytes, potentially contributing to vascular destabilization, and opens new avenues for studying genetic forms of human cerebral small vessel disease.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Medicine – Biochemistry and Molecular Biology

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2024

Author dc:creator

• Graff, Merry Faye

Advisor dc:contributor.advisor

• Childs, Sarah

Committee members dc:contributor.committeemember

• McFarlane, Sarah
• Grewal, Savraj

• Pericytes
• Vascular Stability
• Foxf2
• Zebrafish
• Loxl2
• Endothelium
• Cerebral Small Vessel Disease
• Development

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://doi.org/10.11575/PRISM/46641

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/119045