The kinesin-3 family motor KLP-4 regulates anterograde trafficking of GLR-1 glutamate receptors in the ventral nerve cord of C. elegans.
Monteiro, Michael.
2013
-
Abstract: Glutamate
is the major excitatory neurotransmitter in the mammalian brain. Changes in the strength
of glutamatergic synapses are thought to underlie learning and memory and to contribute
to the pathology of numerous neurological diseases. The transport of glutamate receptors
from the cell body to synapses contributes to the regulation of synaptic strength. We
previously showed that ... read morecyclin-dependent kinase-5 (CDK-5) positively regulates the
abundance of fluorescently-tagged GLR-1 glutamate receptors at synapses in the ventral
nerve cord (VNC) of C. elegans. In this thesis I investigate the roles of novel
regulators of GLR-1 abundance in the VNC. In Chapter 2, I generate genetic mutants that
suppress the effects of cdk-5 overexpression on GLR-1 abundance at synapses to identify
genes that regulate GLR-1 abundance in the VNC and that may function in the same
cellular pathway as CDK-5. I identify a mutation in klp-4/KIF13, which encodes a
kinesin-3 family motor as a strong suppressor of increased GLR-1 abundance in animals
that overexpress cdk-5. In Chapter 3, I characterize the novel kinesin motor KLP-4 and
its role in GLR-1 trafficking. I find that klp-4 mutants have decreased abundance of
GLR-1 at synapses in the VNC. Time-lapse microscopy indicates that klp-4 and cdk-5
mutants exhibit decreased anterograde trafficking of GLR-1. I conduct genetic analyses
on klp-4 mutants with loss and gain of function of cdk-5 and find that KLP-4 and CDK-5
function in the same pathway to regulate GLR-1 in the VNC. Interestingly, I find that
loss of function of KLP-4 affects GLR-1 levels in the cell body differently than loss of
function of CDK-5. GLR-1 abundance increases in cell bodies of cdk-5 mutants but is
unchanged in klp-4 mutants. However, GLR-1 does accumulate in klp-4 mutant cell bodies
if receptor degradation in the MVB/lysosome pathway is blocked, suggesting that in the
absence of its KLP-4 motor, GLR-1 is degraded. Finally, in Chapter 4, I investigate
potential mechanisms for control of KLP-4 activity and identify a microRNA family,
mir-75/mir-79 and the kinesin-1 motor, unc-116/Kif5 as novel regulators of GLR-1
abundance in the VNC.
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Peter Juo.
Committee: Dan Jay, Laura Liscum, Brent Cochran, and Josh Kaplan.
Keywords: Physiology, Neurosciences, and Genetics.read less - ID:
- m900p642f
- Component ID:
- tufts:20463
- To Cite:
- TARC Citation Guide EndNote
