Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly

Anderson, Garret R.; Maxeiner, Stephan; Sando, Richard; Tsetsenis, Theodoros; Malenka, Robert C.; Südhof, Thomas C.

doi:10.1083/jcb.201703042

Cited by 88 publications

(159 citation statements)

References 57 publications

(106 reference statements)

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“…However, Lphn2-expressing cells aggregated with Ten3-expressing cells (Extended Data Fig. 5c), consistent with previously reported heterophilic interaction between Teneurins and Latrophilins 5,7,17,29,31 . The heterophilic interaction of Lphn2 and Ten3 combined with their striking complementary expression in lateral versus medial subnetworks suggests that the interaction between Lphn2 and Ten3 may result in repulsion, which could enhance the targeting precision of the lateral and medial hippocampal networks.…”

Section: Ten3+ Ca1 Axons Avoid Lphn2+ Targetssupporting

confidence: 91%

“…3b). We also examined protein expression by using an anti-Ten3 antibody 5 and an anti-GFP antibody in Lphn2-Venus-knockin mice 31 . In all regions, Lphn2 and Ten3 proteins were inversely expressed in the synaptic layers corresponding to their mRNA expression, including molecular layer of CA1, cell body and molecular layers of the subiculum, and layer III of the entorhinal cortex ( Fig.…”

Section: Inverse Expression Of Lphn2 and Ten3mentioning

confidence: 99%

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Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks

Pederick

Lui

Gingrich

et al. 2020

Preprint

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Spatial-and object-related signals are preferentially processed through the medial and lateral hippocampal networks (MHN and LHN), respectively 1,2 . MHN comprises interconnected medial entorhinal cortex, proximal CA1 (pCA1), and distal subiculum (dSub), whereas the LHN comprises interconnected lateral entorhinal cortex, distal CA1, and proximal subiculum 3,4 . Previously, we showed that Teneurin-3 (Ten3) has matching expression in all interconnected regions of the MHN and is required in both CA1 and subiculum for the precise pCA1→dSub axon targeting through homophilic attraction 5 . Can matching gene expression in interconnected nodes of the LHN also contribute to hippocampal network assembly? Here, we discovered that latrophilin-2 (Lphn2), an adhesion GPCR known to bind teneurins 6-8 , has matching expression in the LHN that is complementary to Ten3. Viral-genetic perturbations in vivo revealed that Ten3+ pCA1 axons are repelled by ectopic expression of Lphn2 in dSub, and ectopically invade proximal subiculum deleted for Lphn2. Simultaneous subiculum deletion of Lphn2 and Ten3 causes Ten3+ pCA1 axon mistargeting reflecting loss of both repulsion and attraction. Our findings demonstrate that Lphn2 acts as a repulsive ligand for Ten3+ axons, identify Ten3 as a receptor for both repulsive and attractive ligands in the same axon during target choice, and reveal how a 'Ten3→Ten3, Lphn2→Lphn2' rule directs the precise assembly of functional hippocampal networks.In order for the central nervous system to accurately process information, neurons must connect precisely with their correct targets. Neuronal circuit assembly can generally be divided into three steps: 1) axons are guided to the appropriate anatomical region; 2) axons select specific target neurons within the region; and 3) axons form synapses with target neurons 9 . Molecular mechanisms underlying axon guidance and synapse formation/organization have been revealed over the last several decades 10-12 . Less is known about the mechanisms of target selection, particularly in complex circuits of the central mammalian brain. The differential expression of cell surface molecules plays a critical role in allowing discrete neuronal circuits to be formed precisely 9,13 . For example, a pair of evolutionarily conserved type II transmembrane proteins,

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Section: Ten3+ Ca1 Axons Avoid Lphn2+ Targetssupporting

confidence: 91%

Section: Inverse Expression Of Lphn2 and Ten3mentioning

confidence: 99%

Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks

Pederick

Lui

Gingrich

et al. 2020

Preprint

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“…1B) (Deak et al, 2009;Krasnoperov et al, 1997;Lelianova et al, 1997;Sudhof, 2001;Sugita et al, 1999). Lphn's have roles in embryogenesis, tissue polarity, synaptic development and neural circuit connectivity, interestingly almost identical to the functions of Tenm's (Anderson et al, 2017;Boucard et al, 2014;Deak et al, 2009;Hamann et al, 2015;Krasnoperov et al, 1997;Lelianova et al, 1997; In agreement with in vivo transgenic mice experiments, only the splice variant of Tenm2 that can interact with Lphn3 (Tenm2 -SS) was able to promote excitatory synapses when co-expressed with FLRT3 in cultured neurons in vitro (Fig. 1C, left) (Sando et al, 2019).…”

Section: Introductionsupporting

confidence: 66%

Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism

Xie²,

Cornelius

et al. 2020

Preprint

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The trans-synaptic interaction of the cell-adhesion molecules teneurins (Tenm's) with latrophilins (Lphn's) promotes excitatory synapse formation when Lphn's simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within Tenm's abolishes the Tenm-Lphn interaction and switches Tenm function to specify inhibitory synapses. How Tenm's bind to Lphn's in a manner regulated by alternative splicing remains unclear. Here, we report the high-resolution cryo-EM structure of the Tenm2-Lphn3 complex, and describe the trimeric Tenm2-Lphn3-FLRT3 complex. The structure reveals that the N-terminal lectin-like domain of Lphn3 binds to the Tenm2 barrel at a site far away from the alternatively-spliced region. Alternative-splicing regulates the Tenm2-Lphn3 interaction by hindering access to the Lphn-binding surface rather than altering it. Strikingly, mutagenesis of the Lphn-binding surface of Tenm2 abolishes the Lphn3 interaction and impairs excitatory but not inhibitory synapse formation. These results suggest that a multi-level coincident binding mechanism mediated by a cryptic adhesion complex between Tenm's and Lphn's regulates synapse specificity.

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“…However, a presynaptic localization for latrophilins was difficult to reconcile with their trans-interaction with neurexins, which as presynaptic proteins would have to interact with postsynaptic latrophilins (Boucard et al, 2012). Recently, conditional Lphn2 KO mice showed that postsynaptic, but not presynaptic deletion of Lphn2 in CA1-region pyramidal neurons causes a severe decrease in excitatory synapse density and excitatory synaptic transmission (Anderson et al, 2017). In these CA1-region neurons, Lphn2 was localized preferentially to postsynaptic spines in the S. lacunosum-moleculare.…”

Section: Latrophilinsmentioning

confidence: 99%

“…In these CA1-region neurons, Lphn2 was localized preferentially to postsynaptic spines in the S. lacunosum-moleculare. In vivo deletion of Lphn2 from CA1-region pyramidal neurons caused a selective loss only of spines and synapses in the S. lacunosum-moleculare but not the S. oriens or S. radiatum as analyzed morphologically and electrophysiologically (Anderson et al, 2017). These experiments suggest that latrophilins may function as postsynaptic recognition molecules for incoming axons in a defined dendritic domain.…”

Section: Latrophilinsmentioning

confidence: 99%

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Südhof

2017

Cell

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637

718

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Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, that thereby determines the precise responses of synapses to spike patterns in a neuron and circuit, and that is vulnerable to impairments in neuropsychiatric disorders.

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Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly

Cited by 88 publications

References 57 publications

Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks

Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks

Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

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