Presynaptic integrin signaling in synaptic structural plasticity
Date Issued
2010
Date
2010
Author(s)
Tsai, Pei-I
Abstract
Integrin signaling involves in several different cellular processes, including migration, adhesion, survival and proliferation. In neurons, integrin participates in neurite outgrowth, axonal guidance, synaptic formation and synaptic plasticity. During hippocampus neuron synaptic development and maintenance, postsynaptic expressed integrin functions a critical role to set the synaptic property. In this dissertation, I identify the function and regulation mechanism of presynaptic integrin singaling in synaptic structural plasticity. Through the isolation of Drosophila fak, Fak56, mutants, I find FAK signaling is specifically required in presynaptic cell to confine synaptic growth at Drosophila neuromuscular junctions (NMJs). In genetic analyses, integrin αPS3βν and Src kinases are suggested to participate in this presynaptic FAK signaling. To dissect the mechanism, Erk activity is upregulated at NMJs of Fak56 mutants. Consistently, Fas2, Erk downstream target gene, is also affected in Fak56 mutants. Following that, both RasGAP domain containing genes, vap and NF1, are identified in Fak56 genetic modifier screening. Fak56 forms complex with NF1, but not Vap. Surprisingly, NF1 downstream cAMP pathway, but not Ras signaling, is required for its function in synaptic structural plasticity under Fak56 regulation. Under experience-induced synaptic potentiation condition, I find this intergin/Fak56/NF1 signaling activity modulates the structural plasticity. Furthermore, LanA, Laminin α subunit, localizes at synaptic clefts of peri-active zone and triggers presynaptic integrin signaling activation at NMJs. Only postsynaptic expressed LanA can localize at synaptic clefts and modulate presynaptic integrin signaling. Interestingly, LanA levels at synaptic clefts depend on neuronal activity. These data suggests that retrograde LanA triggers presynaptic integrin signaling in confining synaptic structural plasticity. As all above, my studies provide a new insight of integrin signaling in synaptic structural plasticity that may contribute to both experience-induced neuronal dynamic and molecular regulation mechanism of NF1 synaptic defects and learning disability.
Subjects
FAK
expreience-dependent synaptic strutural plasticity
integrin
retrograde signaling
Laminin
Type
thesis
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