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Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain
Xiao Yong Yang1, Robert E Stanley1, Adam P Ross1
1Department of Psychiatry, University of California, San Francisco (UCSF), San Francisco, CA, USA.
Cerebral Cortex (New York, N.Y. : 1991)
|January 3, 2018
Summary
SEC14 and Spectrin domain-1 (Sestd1) is a key synapse protein regulating neuronal development. Its absence impairs dendrite and synapse formation by affecting Rho GTPases in the mouse hippocampus.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- SEC14 and Spectrin domain-1 (Sestd1) is a synaptic protein.
- Sestd1 exhibits a dynamic shift from presynaptic to postsynaptic localization during neuronal maturation in the mouse hippocampus.
Purpose of the Study:
- To investigate the role of Sestd1 in the neurodevelopment of hippocampal pyramidal neurons.
- To elucidate the molecular mechanisms underlying Sestd1's function in synapse formation and regulation.
Main Methods:
- Genetic deletion of Sestd1 in mice.
- Analysis of neuronal morphology (dendrite arbors, spines) and excitatory synapse density.
- Electrophysiological recordings of AMPA- and NMDA-excitatory postsynaptic currents.
- Co-immunoprecipitation and mass spectrometry to identify protein interactions.
Main Results:
- Global genetic deletion of Sestd1 led to reduced dendrite arbors, spines, and excitatory synapses in hippocampal pyramidal neurons.
- Sestd1 deletion resulted in cell-autonomous reductions in AMPA- and NMDA-excitatory postsynaptic currents.
- Deficits were associated with increased activation of Rho family GTPases, Rac1 and RhoA.
- Sestd1 was found to form complexes with the Rho GTPase activating protein (GAP), Breakpoint Cluster Region protein, and other GAPs/guanine nucleotide exchange factors.
Conclusions:
- Sestd1 acts as a developmentally regulated synaptic regulator of Rho GTPases.
- Sestd1 is crucial for the formation of dendrites and excitatory synapses in developing forebrain pyramidal neurons.
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