Teneurin-3 controls topographic circuit assembly in the hippocampus

Berns, Dominic S.; DeNardo, Laura A; Pederick, Daniel T.; Luo, Liqun

doi:10.1038/nature25463

Cited by 130 publications

(222 citation statements)

References 66 publications

(86 reference statements)

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“…Most studies of selective synapse formation have focused on cell-cell recognition between neurons. Several families of neuronal cell adhesion molecules and secreted proteins have been shown to play important roles in synapse specificity (Berns et al, 2018;Chih et al, 2006;Duan et al, 2014;Krishnaswamy et al, 2015;Tran et al, 2009;Zipursky and Sanes, 2010). However, it remains unclear whether the specificity of synapse formation can be entirely explained by an adhesion code among circuit partners, or if other cellular and molecular mechanisms also play an instructive role.…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

Koh¹,

Eroglu

et al. 2019

Preprint

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Glial cells regulate synaptic connectivity during development, but whether they selectively instruct the formation of specific synaptic circuits is not known. Here we show that the major perisynaptic glia of the retina, the Muller glia (MG), control the proper establishment of the direction-selective (DS) circuit by a synaptogenic protein, Thrombospondin 1 (TSP1). We found that TSP1 promotes excitatory synapse formation specifically in on-off Direction-Selective retinal Ganglion Cells (ooDSGCs). Lack of TSP1 leads to reduced synapse formation within the inner plexiform sublayers containing DS-circuit, resulting in deficits of ooDSGC function. Even though pan-TSP receptor, α2δ-1, interaction is required for TSP1-induced synapse formation, the ooDSGC-subtype specificity of TSP1 is conferred by a second neuronal TSP1 receptor, β1-Integrin. Furthermore, conditional deletion of β1-Integrin in ooDSGCs results in diminished excitatory synapse formation without disturbing laminar organization showing that MG-secreted TSP1 controls circuitspecific synapse formation via β1-Integrin.

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Section: Introductionmentioning

confidence: 99%

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

Koh¹,

Eroglu

et al. 2019

Preprint

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“…To ensure evolutionary economy, these events can be coordinated through reuse of molecular cues and mechanisms. These mechanisms are conserved from peripheral to central synapses in Drosophila; work has also shown similar roles in mammalian nervous systems for wiring and synapse organization (Berns et al, 2018;Dharmaratne et al, 2012;Leamey et al, 2007;Mosca, 2015), suggesting mechanistic conservation across multiple species as well. As such, the Teneurins are an evolutionary constant, working at multiple levels to ensure nervous system development.…”

Section: Future Directionsmentioning

confidence: 87%

The Tenets of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes in the Drosophila Nervous System

DePew

Aimino

Mosca

2018

Preprint

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To successfully integrate a neuron into a circuit, a myriad of developmental events must occur correctly and in the correct order. Neurons must be born and grow out towards a destination, responding to guidance cues to direct their path. Once arrived, each neuron must segregate to the correct sub-region before sorting through a milieu of incorrect partners to identify the correct partner with which they can connect. Finally, the neuron must make a synaptic connection with their correct partner; a connection that needs to be broadly maintained throughout the life of the animal while remaining responsive to modes of plasticity and pruning. Though many intricate molecular mechanisms have been discovered to regulate each step, recent work showed that a single family of proteins, the Teneurins, regulates a host of these developmental steps in Drosophilaan example of biological adaptive reuse. Teneurins first influence axon guidance during early development. Once neurons arrive in their target regions, Teneurins enable partner matching and synapse formation in both the central and peripheral nervous systems. Despite these diverse processes and systems, the Teneurins use conserved mechanisms to achieve these goals, as defined by two tenets: 1) transsynaptic interactions with each other and 2) membrane stabilization via an interaction and regulation of the cytoskeleton. These processes are further distinguished by 1) the nature of the transsynaptic interaction -homophilic interactions (between the same Teneurins) to engage partner matching and heterophilic interactions (between different Teneurins) to enable synaptic connectivity and the proper apposition of pre-and postsynaptic sites and 2) the location of cytoskeletal regulation (presynaptic cytoskeletal regulation in the CNS and postsynaptic regulation of the cytoskeleton at the NMJ). Thus, both the roles and the mechanisms governing them are conserved across processes and synapses. In this review, we will highlight the contributions of Drosophila synaptic biology to our understanding of the Teneurins and discuss the mechanistic conservation that allows the Teneurins to achieve common neurodevelopmental goals. Finally, we will posit the next steps for understanding how this remarkably versatile family of proteins functions to control multiple distinct events in the creation of a nervous system.DePew Aimino et al.

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“…As alternative splicing prevents the formation of the Tenm2/Lphn3 interaction by hiding it rather than destroying it, it is plausible that the +SS isoform enables other Tenm2 interactions that the -SS isoform cannot mediate. Indeed, the trans-dimerization of Tenm2 was reported to occur only by the +SS isoform (Berns et al, 2018); and previous studies suggested that Tenm2 +SS isoform should interact with unknown ligands in order to induce inhibitory synapses (Li et al, 2018). This speculative model explains the currently available data.…”

Section: Discussionmentioning

confidence: 99%

“…1C) (Feng et al, 2002;Oohashi et al, 1999;Vysokov et al, 2016). Tenm's have central roles in tissue polarity, embryogenesis, heart development, axon guidance, and synapse formation (Berns et al, 2018;Boucard et al, 2014;Doyle et al, 2006;Hong et al, 2012;Levine et al, 1994;Mosca and Luo, 2014;Silva et al, 2011;Woelfle et al, 2016); and are linked to various diseases including neurological disorders, developmental problems, various cancers and congenital general anosmia (Aldahmesh et al, 2012;Alkelai et al, 2016;Chassaing et al, 2016;Graumann et al, 2017;Hor et al, 2015;Talamillo et al, 2017;Ziegler et al, 2012). Lphn's (Lphn1-3 in mammals) belong to the adhesion-type Gprotein coupled receptor (GPCR) family (Krasnoperov et al, 1996;Lelianova et al, 1997) (Sugita et al, 1999) and have a large N-terminal ECR (>800 amino acids) in addition to their signaling seven-pass transmembrane domain and cytoplasmic tail ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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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Teneurin-3 controls topographic circuit assembly in the hippocampus

Cited by 130 publications

References 66 publications

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

The Tenets of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes in the Drosophila Nervous System

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

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