Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships

Zhang, Peng; Lu, H. Peter; Peixoto, Rui T.; Pines, Mary; Ge, Yuan; Oku, Shinichiro; Siddiqui, Tabrez J.; Xie, Yicheng; Wu, Wen-Lan; Archer-Hartmann, Stephanie; Yoshida, Kouji; Tanaka, Kenji F.; Aricescu, A. Radu; Azadi, Parastoo; Gordon, Michael D.; Sabatini, Bernardo L.; Wong, Rachel; Craig, Ann Marie

doi:10.1016/j.cell.2018.07.002

Cited by 131 publications

(192 citation statements)

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“…Therefore, it is also possible that Wg and Dlp regulate the starvation-induced synaptic and behavioral plasticities. Furthermore, a recent study revealed that neurexin synaptic organizing proteins are expressed as HSPGs (Zhang et al, 2018). HS modifications in presynaptic neurexins are critical for high-affinity interactions with the postsynaptic ligands neuroligins and the leucine-rich repeat transmembrane neuronal proteins (LRRTMs), and are essential for synapse development at the mouse hippocampus (Zhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent study revealed that neurexin synaptic organizing proteins are expressed as HSPGs (Zhang et al, 2018). HS modifications in presynaptic neurexins are critical for high-affinity interactions with the postsynaptic ligands neuroligins and the leucine-rich repeat transmembrane neuronal proteins (LRRTMs), and are essential for synapse development at the mouse hippocampus (Zhang et al, 2018). Drosophila Neurexin (Dnrx) is also an HSPG and positively regulates larval locomotion speed and type I bouton growth at NMJs in an HS-dependent manner (Zhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…HS modifications in presynaptic neurexins are critical for high-affinity interactions with the postsynaptic ligands neuroligins and the leucine-rich repeat transmembrane neuronal proteins (LRRTMs), and are essential for synapse development at the mouse hippocampus (Zhang et al, 2018). Drosophila Neurexin (Dnrx) is also an HSPG and positively regulates larval locomotion speed and type I bouton growth at NMJs in an HS-dependent manner (Zhang et al, 2018). Furthermore, it has been suggested that Dnrx, Neuroligin (Dnlg1), and Wit form signaling complexes at the NMJ (Banerjee et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

et al. 2019

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Graphical Abstract Highlights d Octopaminergic signaling regulates postsynaptic Dlp levels during starvation d dlp is required for starvation-induced synaptic growth and locomotor behavior d Dlp regulates GluRIIA-mediated non-canonical BMP signaling d This BMP signaling regulates starvation-induced behavioral and synaptic plasticities SUMMARYUnder food deprivation conditions, Drosophila larvae exhibit increases in locomotor speed and synaptic bouton numbers at neuromuscular junctions (NMJs). Octopamine, the invertebrate counterpart of noradrenaline, plays critical roles in this process; however, the underlying mechanisms remain unclear. We show here that a glypican (Dlp) negatively regulates type I synaptic bouton formation, postsynaptic expression of GluRIIA, and larval locomotor speed. Starvation-induced octopaminergic signaling decreases Dlp expression, leading to increases in synapse formation and locomotion. Dlp is expressed by postsynaptic muscle cells and suppresses the non-canonical BMP pathway, which is composed of the presynaptic BMP receptor Wit and postsynaptic GluRIIA-containing ionotropic glutamate receptor. We find that during starvation, decreases in Dlp increase non-canonical BMP signaling, leading to increases in GluRIIA expression, type I bouton number, and locomotor speed. Our results demonstrate that octopamine controls starvation-induced neural plasticity by regulating Dlp and provides insights into how proteoglycans can influence behavioral and synaptic plasticity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

et al. 2019

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“…We also reveal that Neurexin-Robo interaction requires heparin-conjugated moieties and that the synaptogenic activity of Robo is abolished by treatment with heparinase. Since Neurexin1 was recently shown to require a rare glycan modification, heparan sulfate 35 , this posttranslational modification might also participate in increasing the specificity of trans-synaptic interactions between Robo, Slit and Neurexins. Future experiments will need to provide insights into the structure of this and other trans-synaptic protein complex in order to gain further evidence for this coincidence detection model as a mechanism to increase synaptic specificity.…”

Section: Trans-synaptic Coincidence Detection As a Molecular Mechanismentioning

confidence: 99%

Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

Blockus

Rolotti

Szoboszlay

et al. 2019

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The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via itsIg4-5 domains. In vivo 2-photon Ca 2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.Proper circuit function relies on the establishment of synaptic connections characterized by a high degree of cell type and subcellular specificity. How this striking degree of synaptic specificity is achieved during development remains poorly understood, especially in the complex brains of mammals. Many cell surface molecules that mediate molecular recognition between axons and dendrites during circuit development have been identified 1-4 . These trans-synaptic adhesion molecules are often expressed in a cell-type specific manner 5 thereby determining the pool of a cell's possible synaptic partners. Some classes of these molecules have synaptic organizing properties evidenced by their direct or indirect ability to recruit key pre-and postsynaptic proteins. When axons reach their target areas, a cellular switch from a phase of growth and branching to synaptogenesis is observed. This switch is characterized by dynamic instability of adhesion progressively leading to more stable patterns of synaptic connectivity characterizing adult circuits. One of the foremost outstanding questions in neuroscience is how synapse formation is mechanistically integrated with earlier developmental steps such as axon guidance 3 and branching. One potential mechanism for coordinating this transition relies on the possibility that axon guidance cues acquire synaptogenic functions during circuit wiring. Indeed, evidence for such dual use of developmental molecules has been reported 6 . However, it remains unclear what prompts molecules to switch their function from axon guidance to synaptogenesis.Here we report that the well-studied axon guidance ligand-receptor pair Sl...

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“…For example, LRRTMs specifically bind to Nrx (SS4-), Cblns bind to Nrx (SS4+), C1qls bind to Nrx3 (SS5 25b ), dystroglycan bind to Nrx (SS2-and SS4-), and IgSF21 bind to Nrx2a (LNS1) (Sü dhof, 2017; Tanabe et al, 2017;Yuzaki, 2018). Now, Zhang et al, 2018, this issue of Cell provide compelling evidence that Nrxs themselves are heparan sulfate proteoglycans (HSPGs), joining a superfamily of 17 HSPGs (Xu and Esko, 2014). Since HSPGs interact with various HS binding proteins (Condomitti and de Wit, 2018), HS chain-dependent sugar code, in addition to isoform-dependent protein code, likely provide Nrxs with more synaptic binding partners with multifarious functions.…”

mentioning

confidence: 99%