Roles of the cytoskeletal regulatory protein Farp1 in forebrain development and activity-dependent synapse remodeling.
Coleman, Andrew.
2019
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The function of the
central nervous system relies on the proper establishment, maintenance and refinement of
the morphological features of neurons, including the specialized points of contact
between cells, known as synapses. Key to the exquisite control of neuronal morphology is
the regulation of the actin cytoskeleton, a collection of dynamic structures in neurons
capable of regulating ... read moreneuronal morphology as well as cellular organization. Dynamic
regulation of actin assembly is critically controlled by the Rho GTPases, molecular
protein switches required for the establishment of neuronal morphology and synaptic
plasticity. Rho GTPases are acutely regulated by diverse sets of signaling proteins that
are capable of coupling changes in the cellular environment to changes in the actin
cytoskeleton and cell function. Several regulators of Rho GTPase signaling are expressed
in the developing brain, but how and to what extent these signaling proteins work in
concert to contribute to brain development and mature brain function remain incompletely
understood. This work focuses on extending previous knowledge of the cytoskeletal
regulator Farp1, an activator of the Rho GTPase Rac1. Building on previous work
demonstrating the roles of Farp1 in regulating the development of hippocampal dendrite
complexity and excitatory synapse density, these studies establish that Farp1
contributes to these processes in vivo in the developing mouse hippocampus. Farp1 is
required for normal levels of dendritic spine density and dendritic arbor complexity in
the developing mouse hippocampus, establishing the role of additional Rac1 activator
necessary for normal brain development. These studies also identify how the signaling
roles of Farp1 at synapses are modulated by activity dependent signaling at synapses.
Characterization of the role of an activity-dependent phosphorylation site in Farp1
identified the role this phosphorylation site plays in regulating the ability of Farp1
to activate Rac1, plasticity-induced increases in the cell surface levels of glutamate
receptors, and plasticity-induced changes in the postsynaptic actin cytoskeleton. These
results expand knowledge of the dynamic regulatory mechanisms controlling Rac1
activation necessary for synaptic plasticity. Collectively these studies increase the
understanding of the complex nature of the control of Rho GTPase signaling required for
brain development and synaptic plasticity.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Neuroscience.
Advisor: Thomas Biederer.
Committee: Yongjie Yang, Michele Jacob, Peter Juo, and Jeff Cottrell.
Keywords: Neurosciences, Cellular biology, and Biology.read less - ID:
- ww72bq69p
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