Advisory Committee Chair
Anne Theibert
Advisory Committee Members
Candice Floyd
Lucas Pozzo-Miller
Kevin Roth
Scott Wilson
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
In the nervous system, PI 3-kinase has been implicated in neuronal differentiation. My studies have focused on a candidate neuronal PI 3-kinase target centaurin alpha-1, which binds PtdIns(3,4,5)P3, and is an Arf6 GAP. Centaurin alpha-1 is localized in dendrites, dendritic spines and synapses, and is required for neuronal differentiation and spine morphogenesis. In dissociated neuronal cultures, expression of centaurin alpha-1 enhances dendritic branching, and increases dendritic filopodia, lamellipodia and spine-like protrusions. Expression of centaurin alpha-1 GAP inactive mutant or knocking down centaurin alpha-1 levels using siRNA leads to inhibition of dendritic outgrowth and branching. Manipulations of centaurin alpha-1 also disrupt spine morphogenesis in organotypic brain slice cultures. The effects of centaurin alpha-1 on dendritic development are dependent on it functioning through regulation of Arf6. The constitutively GTPbound mutant Arf6, which reduces dendritic branching on its own, is able to reverse the effects of centaurin alpha-1 overexpression. Conversely, expression of the GDP-bound mutant, Arf6, which enhances branching and outgrowth on its own, can prevent the loss of dendrites induced by centaurin alpha-1 GAP inactive mutant expression or siRNA knock down. Arf6 has been shown to regulate Rac1, and both Arf6 and centaurin alpha- 1 have been proposed to regulate ERK; both Rac1 and ERK have been implicated in neuronal differentiation. Thus, I examined whether centaurin alpha-1 modulates neuronal Rac1 and ERK, to identify candidate downstream effectors of centaurin alpha-1 and Arf6 iii in neuronal differentiation. ERK and Rac1 activation are enhanced in centaurin alpha-1 over-expressing neurons and this activation is dependent on centaurin alpha-1 GAP activity. As a regulator of Arf6, centaurin alpha-1 has emerged as a candidate to participate in PI 3-kinase regulated Arf6 pathways that control dendritic differentiation and spine morphogenesis.
Recommended Citation
Moore, Carlene Drucilla, "The Role Of Centaurin Alpha-1 In The Regulation Of Neuron Al Differentiation" (2008). All ETDs from UAB. 3764.
https://digitalcommons.library.uab.edu/etd-collection/3764