THESIS
2018
xiii, 68 pages : illustrations (some color) ; 30 cm
Abstract
Synaptogenesis is an exquisite process in which synaptic contacts establish
between neurons. The locations, numbers and types of synapses are under precise
regulation during synaptogenesis, to ensure the homeostasis of nervous system is
maintained. The molecular mechanisms underlying synapse formation and the
specification of synapse diversity is not fully understood. Although some related
adhesion molecules and scaffold proteins in synapse have been implicated in synapse
formation, the details of their roles in synaptogenesis are still needed to be investigated.
In this study, we identified that SORBS1 specifically localizes with PSD-95
(postsynaptic density protein 95) at excitatory synapses. Knocking down of SORBS1
in neurons impairs spine formation. This defect in spine mo...[
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Synaptogenesis is an exquisite process in which synaptic contacts establish
between neurons. The locations, numbers and types of synapses are under precise
regulation during synaptogenesis, to ensure the homeostasis of nervous system is
maintained. The molecular mechanisms underlying synapse formation and the
specification of synapse diversity is not fully understood. Although some related
adhesion molecules and scaffold proteins in synapse have been implicated in synapse
formation, the details of their roles in synaptogenesis are still needed to be investigated.
In this study, we identified that SORBS1 specifically localizes with PSD-95
(postsynaptic density protein 95) at excitatory synapses. Knocking down of SORBS1
in neurons impairs spine formation. This defect in spine morphogenesis could be
rescued by introducing shRNA-resistant SORBS1, indicating that SORBS1 regulates
spine morphogenesis in neurons. Phosphorylation levels of WAVE1 (Wiskott-Aldrich
syndrome protein family member 1) and PAK1 (α-p21-activated kinase 1) increase significantly in SORBS1-KD neurons, suggesting that abnormal actin polymerization
and depolymerization might contribute to the abnormality in spine morphology.
Inhibiting WAVE1 function by targeting it to mitochondria could partially rescue the
defects in SORBS1-KD neurons. Taken together, we considered that SORBS1 localizes
and functions in excitatory synapses, and could regulate the spine morphology through
WAVE1-Arp2/3 pathway.
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