On the Teneurin track: a new synaptic organization molecule emerges

Mosca, Timothy J.

doi:10.3389/fncel.2015.00204

Cited by 61 publications

(85 citation statements)

References 181 publications

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“…Synaptic organizers like Neurexins / Neuroligins, Teneurins, protein tyrosine phosphatases (PTPs), leucine rich repeat transmembrane proteins (LRRTMs), and Ephrin / Eph receptors, among others, ensure the proper number, distribution, and function of synaptic connections (Hruska and Dalva, 2012; Mosca, 2015; Siddiqui and Craig, 2011; Südhof, 2008; Takahashi and Craig, 2013; de Wit and Ghosh, 2016). Loss-of-function mutations in these key synaptogenic molecules have deleterious structural, functional, and organizational consequences for synapses and circuits.…”

Section: Introductionmentioning

confidence: 99%

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

Mosca

Luginbuhl

Wang

et al. 2017

eLife

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Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.DOI: http://dx.doi.org/10.7554/eLife.27347.001

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Section: Introductionmentioning

confidence: 99%

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

Mosca

Luginbuhl

Wang

et al. 2017

eLife

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“…These genes are orthologues of the fly odd oz/teneurin genes ten-a and ten-m , which function in synaptic connectivity in the olfactory and neuromuscular systems (reviewed in [34]). In mammals, they have both homophilic and heterophilic interactions.…”

Section: Resultsmentioning

confidence: 99%

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

et al. 2017

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The thalamus or “inner chamber” of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity.

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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: 88%

“…This may occur via modulation of the cytoskeleton (Zheng et al, 2011) at both the NMJ and in the CNS, revealing a fascinating instance of mechanistic conservation. Their widespread expression in both invertebrate and vertebrate systems (Antinucci et al, 2013;Dharmaratne et al, 2012;Feng et al, 2002;Kenzelmann et al, 2008;Li et al, 2006;Mörck et al, 2010;Mosca, 2015;Zhang et al, 2018) and conservation of protein structure and mechanistic function (Jackson et al, 2018) suggests they may represent a general and versatile matching mechanism across synapse types and evolutionary taxa.…”

Section: Partner Matchingmentioning

confidence: 99%

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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On the Teneurin track: a new synaptic organization molecule emerges

Cited by 61 publications

References 181 publications

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

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

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