Advisory Committee Chair
Harald Sontheimer
Advisory Committee Members
Burt Nabors
Michelle Olsen
Lucas Pozzo-Miller
Linda Wadiche
Document Type
Dissertation
Date of Award
2013
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
A limited amount of migration occurs in the adult brain, including migration of neuroblasts during adult neurogenesis and pathological migration of primary brain tumors. Ion channels are commonly utilized during migration to allow shape and volume changes required for cell movement, and we specifically examine the role of KCa3.1 in the adult brain. These channels are well-suited to facilitate movement because they respond to common migration signals, i.e. intracellular Ca2+ changes, and efflux K+, allowing the outflow of water and cell volume regulation. Our findings suggest that KCa3.1 is highly expressed in migratory cells, adult neuroblasts and glioma cells, but less so in normal brain. Glioma cells are highly invasive, which is partially responsible for poor patient prognosis. We first confirmed functional expression of KCa3.1 in multiple patient-derived glioma lines. Inhibition or knockdown of KCa3.1 decreased migration, assessed by in vitro transwell migration assay, in situ live invasion assay, and in vivo glioma implantation into mice. Furthermore, research into patient data shows a significant decrease in survival correlated with upregulation of KCa3.1, indicating an important role for KCa3.1 in glioma migration. During adult neurogenesis, neuroblasts migrate from the subventricular zone to become neurons in the olfactory bulb (OB), traveling along the rostral migratory stream (RMS). Neuroblasts in the RMS express KCa3.1, which is lost once cells mature in the OB. These cells undergo saltatory migration, and inhibition of KCa3.1 in situ decreases the time cells spend moving, not the migration speed. Blocking TRP channels, the likely Ca2+ source for KCa3.1, similarly decreases migration. Inhibition of KCa3.1 in vivo also leads to an overall decrease in migration. We hypothesize that KCa3.1 is similarly utilized by gliomas and neuroblasts during adult brain migration, possibly because neuroblasts are the source of primary brain tumors, and/or because KCa3.1 is common for the migration machinery of many cell types. We also propose KCa3.1 as a therapeutic target, not only to slow glioma metastasis, but also to enhance cell growth and recovery during brain injury, degeneration, or other insult.
Recommended Citation
Turner, Kathryn L., "Role Of Kca3.1, A Calcium-Activated Potassium Channel, In Cell Migration In The Adult Brain" (2013). All ETDs from UAB. 3182.
https://digitalcommons.library.uab.edu/etd-collection/3182