Intact synapse structure and function after combined knockout of PTPδ, PTPσ and LAR

AbstractIt has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins for the control of synapse assembly. Their synaptic nanoscale localization, however, has not been established, and the fine structure of synapses after knockout of the three vertebrate genes for LAR-RPTPs (PTPδ, PTPσ and LAR) has not been tested. Here, we find that PTPδ is precisely apposed to postsynaptic scaffolds at excitatory and inhibitory synapses using superresolution microscopy. We generated triple-conditional knockout mice for PTPδ, PTPσ and LAR to test whether they are essential for synapse structure. While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. We conclude that LAR-RPTPs, despite their localization at synaptic appositions, are dispensable for the organization and function of presynaptic nerve terminals.

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Intact synapse structure and function after combined knockout of PTPδ, PTPσ and LAR

eLife ◽

10.7554/elife.66638 ◽

2021 ◽

Vol 10 ◽

Author(s):

Javier Emperador-Melero ◽

Giovanni de Nola ◽

Pascal S Kaeser

Keyword(s):

Active Zone ◽

Protein Tyrosine Phosphatases ◽

Synaptic Cleft ◽

Structure And Function ◽

Independent Study ◽

Conditional Knockout ◽

Receptor Protein ◽

Inhibitory Synapses ◽

Superresolution Microscopy ◽

And Function

It has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins that control synapse assembly. Their synaptic nanoscale localization, however, is not established, and synapse fine structure after knockout of the three vertebrate LAR-RPTPs (PTPδ, PTPσ and LAR) has not been tested. Here, superresolution microscopy reveals that PTPδ localizes to the synaptic cleft precisely apposed to postsynaptic scaffolds of excitatory and inhibitory synapses. We next assessed synapse structure in newly generated triple-conditional knockout mice for PTPδ, PTPσ and LAR, complementing a recent independent study of synapse function after LAR-RPTP ablation (Sclip and Südhof, 2020). While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. Hence, despite their localization at synaptic appositions, LAR-RPTPs are dispensable for presynapse structure and function.

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4.The Receptor Protein Tyrosine Phosphatases: Structure And Function

Protein Tyrosine Phosphatases ◽

10.1515/9783110421774-004 ◽

2018 ◽

pp. 119-154

Keyword(s):

Protein Tyrosine Phosphatases ◽

Structure And Function ◽

Receptor Protein ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

And Function ◽

Receptor Protein Tyrosine Phosphatases

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PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1410138112 ◽

2015 ◽

Vol 112 (6) ◽

pp. 1874-1879 ◽

Cited By ~ 55

Author(s):

Ji Seung Ko ◽

Gopal Pramanik ◽

Ji Won Um ◽

Ji Seon Shim ◽

Dongmin Lee ◽

...

Keyword(s):

Synaptic Transmission ◽

Synapse Formation ◽

Transmembrane Protein ◽

Protein Tyrosine Phosphatases ◽

Excitatory Synaptic Transmission ◽

Receptor Protein ◽

Synapse Development ◽

Dependent Manner ◽

And Function ◽

Receptor Protein Tyrosine Phosphatases

Leukocyte common antigen-related receptor protein tyrosine phosphatases—comprising LAR, PTPδ, and PTPσ—are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding–defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

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