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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
PubMed

Insights

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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