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LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses

Abstract

Leukocyte common antigen–related (LAR) family receptor protein tyrosine phosphatases (LAR-RPTP) bind to liprin-α (SYD2) and are implicated in axon guidance. We report that LAR-RPTP is concentrated in mature synapses in cultured rat hippocampal neurons, and is important for the development and maintenance of excitatory synapses in hippocampal neurons. RNA interference (RNAi) knockdown of LAR or dominant-negative disruption of LAR function results in loss of excitatory synapses and dendritic spines, reduction of surface AMPA receptors, impairment of dendritic targeting of the cadherin–β-catenin complex, and reduction in the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). Cadherin, β-catenin and GluR2/3 are tyrosine phosphoproteins that coimmunoprecipitate with liprin-α and GRIP from rat brain extracts. We propose that the cadherin-β-catenin complex is cotransported with AMPA receptors to synapses and dendritic spines by a mechanism that involves binding of liprin-α to LAR-RPTP and tyrosine dephosphorylation by LAR-RPTP.

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Figure 1: Expression pattern and fractionation of LAR-RPTP proteins in rat brain.
Figure 2: Overexpression of LAR interfering constructs reduces the number of excitatory synapses.
Figure 3: LAR interfering constructs decrease the density of dendritic spines.
Figure 4: RNAi knockdown of LAR-RPTP reduces the density of synapses and spines.
Figure 5: Effects of dominant-negative LAR constructs on synaptic function.
Figure 6: Overexpression of LAR and liprin-α interfering constructs disrupt the localization of exogenous GFP–β-catenin.
Figure 7: Effect of protein tyrosine phosphatase and tyrosine kinase inhibitors on synaptic localization of endogenous β-catenin.
Figure 8: Association and tyrosine phosphorylation of cadherin, β-catenin, liprin-α, GRIP, AMPA receptors and LAR-RPTP in rat brain.

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Acknowledgements

The authors thank M. Streuli for kind gifts of LAR, liprin-α1 and liprin-α1A expression constructs, and S. Rudolph-Correia and B. Li for expert help. M.S. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Morgan Sheng.

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Supplementary information

Supplementary Fig. 1

Expression of endogenous LAR-RPTP in cultured hippocampal neurons. (PDF 304 kb)

Supplementary Fig. 2

LAR interfering constructs reduce dendritic spine density in immature hippocampal neurons. (PDF 714 kb)

Supplementary Fig. 3

Overexpression of LAR mutants disrupts surface expression of AMPA receptors and dendritic targeting of β-catenin and cadherin. (PDF 321 kb)

Supplementary Fig. 4

Overexpression of wildtype LAR inhibits the effect of dominant negative LAR mutants on surface AMPA receptors and PSD-95 density. (PDF 402 kb)

Supplementary Fig. 5

Efficacy and specificity of LAR-RPTP RNAi constructs. (PDF 156 kb)

Supplementary Methods (PDF 19 kb)

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Dunah, A., Hueske, E., Wyszynski, M. et al. LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nat Neurosci 8, 458–467 (2005). https://doi.org/10.1038/nn1416

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