- From stem cell to astrocyte: Decoding the regulation of GFAP
P. van Tijn
M.E. van Strien
- Award date
- 16 May 2014
- Number of pages
- Document type
- PhD thesis
- Faculty of Science (FNWI)
- Swammerdam Institute for Life Sciences (SILS)
The research presented in this thesis focuses on glial fibrillary acidic protein (GFAP), the main intermediate filament (IF) in astrocytes and astrocyte subpopulations such as neural stem cells (NSCs). In neurodegenerative diseases or upon brain damage, astrocytes respond to an injury with an upregulation of IF proteins such as GFAP. Expression of GFAP is also highly regulated during development of the mammalian brain, where initiation of GFAP expression induces astrocyte differentiation in NSCs.
The GFAP gene is alternatively spliced, and the canonical isoform GFAPα and an alternative spliced form GFAPδ represent the most abundant isoforms. In contrast to GFAPα, GFAPδ is assembly compromised and its expression levels are a crucial determinant of IF network assembly.
Our research has shown that a specialized GFAP network, induced by expression of an alternatively spliced isoform GFAPδ, modulates astrocyte motility, adhesion, and production of extracellular matrix proteins. Hence, modulation of the GFAP isoform signature modulates astrocyte function, which highlights the importance of a tight regulation of GFAP alternative splicing. In this respect, we unraveled that epigenetic modifications such as histone acetylation and transcriptional regulators, like Notch, are integral components in the control of GFAP isoform expression. Future research will focus on the mechanism of how GFAP, as part of the cytoskeleton, acts as a signaling platform in the cell to regulate vital cellular functions such as proliferation, motility, and adhesion of astrocytes.
- Research conducted at: Universiteit van Amsterdam
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