Nectins and Nectin-like molecules in synapse formation and involvement in neurological diseases

Mizutani, Kiyohito; Miyata, Muneaki; Shiotani, Hajime; Kameyama, Takeshi; Takai, Yoshimi

doi:10.1016/j.mcn.2021.103653

Cited by 15 publications

(10 citation statements)

References 115 publications

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“…These in vitro observations were confirmed by in vivo analyses on Necl3-KO and Necl2/3-dKO mice. However, the present study did not show the evidence that the Necl2/3 trans-interaction is direct and therefore the possibility that this trans-interaction is indirect through other molecules cannot be completely excluded; however, this possibility is unlikely because the direct Necl2/3 transinteraction has been previously shown (Fogel et al, 2007;Mizutani and Takai, 2016;Mizutani et al, 2021). In addition, Necl 2/3 localized at pyramidal cell dendritic spines and mossy fiber axon terminals interacting with these dendritic spines, respectively, possibly mediating mossy fiber axon terminal-dendritic spine interactions (Fig.…”

Section: Discussioncontrasting

confidence: 84%

Necl2/3-mediated mechanism for tripartite synapse formation

et al. 2023

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Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive. We developed an in vitro co-culture system for mouse astrocytes and neurons that induced astrocyte ramifications and PAP formation. Co-cultured neurons were required for astrocyte ramifications in a neuronal activity-dependent manner and synaptically released glutamate and activation of astrocytic mGluR5 metabotropic glutamate receptor were likely involved in astrocyte ramifications. Astrocytic Necl-2/CADM1 trans-interacted with axonal Necl-3/CADM2, inducing astrocyte-synapse interactions and astrocyte functional polarization by recruiting EAAT1/2 glutamate transporters and Kir4.1 K+ channel to the PAPs, without affecting astrocyte ramifications. This Necl-2/3 trans-interaction increased functional synapse number. Thus, astrocytic Necl-2, synaptically released glutamate, and axonal Necl-3 cooperatively formed tripartite glutamatergic synapses in vitro. Studies on hippocampal mossy fiber synapses in Necl-3 knockout and Necl-2/3 double knockout mice confirmed these novel mechanisms for astrocyte-synapse interactions and astrocyte functional polarization in vivo.

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Section: Discussioncontrasting

confidence: 84%

Necl2/3-mediated mechanism for tripartite synapse formation

et al. 2023

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“…In the adult hippocampus where it is most studied, NECTIN3 is found at puncta adherens junctions on dendritic branches and serves as a "latch" to stabilize adjacent synapses. 44,45 Interestingly, in the neonatal hippocampus, NECTIN3 is also found at synaptic junctions before they become morphologically distinct from puncta adherens (Extended Data Fig. 7B).…”

Section: Extension Of Phoxid To the Gaba A R-proximal Proteomementioning

confidence: 96%

Optochemical profiling of receptor-proximal proteins in vivo in minutes

Hamachi,

Takato,

Sakamoto

et al. 2023

Preprint

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Understanding how protein-protein interaction networks in the brain give rise to cognitive functions necessitates their characterization in live animals. However, tools available for this purpose require potentially disruptive genetic modifications and lack the temporal resolution necessary to track rapid changes in vivo. Here, we combined ligand-directed chemistry and photocatalyzed singlet oxygen generation to identify neurotransmitter receptor-proximal proteins in the live mouse brain using only small-molecule reagents and minutes of photoirradiation. Named PhoxID (photooxidation-driven proximity labeling for proteome identification), our method not only recapitulated the known interactomes of two endogenous neurotransmitter receptors (AMPAR and GABAAR) but also uncovered age-dependent shifts, identifying NECTIN3 and IGSF3 as developmentally regulated AMPAR-proximal proteins in the cerebellum. Overall, this work establishes a flexible and generalizable platform to study receptor microenvironments in genetically intact specimens with an unprecedented temporal resolution.

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“…The remaining four members are located in the cell membrane, mediating cell adhesion by homo-or heterodimerization via the interaction of immunoglobin-like domains. 5 For instance, Necl-1 can form a homodimer with itself and heterodimers with other Necls or Nectins, [6][7][8] and Necl-2 can interact with Necl-1, Necl-2, and Necl-3. 8,9 According to previous investigations, Necl-4 is distinctive compared to Necl-1, Necl-2, and Necl-3 because Necl-4 rarely forms a trans-homodimer with itself.…”

Section: Introductionmentioning

confidence: 99%

“…Among those members, Necl‐5 (also known as poliovirus receptor) is closest to Nectin family members (Nectins) at the sequence level, and these molecules can be distinguished on the basis of whether they bind Afadin; binding to Afadin or not is also a difference between Nectins and the other four Necls. The remaining four members are located in the cell membrane, mediating cell adhesion by homo‐ or heterodimerization via the interaction of immunoglobin‐like domains 5 . For instance, Necl‐1 can form a homodimer with itself and heterodimers with other Necls or Nectins, 6–8 and Necl‐2 can interact with Necl‐1, Necl‐2, and Necl‐3 8,9 …”

Section: Introductionmentioning

confidence: 99%

Indispensable role of Nectin‐like 4 in regulating synapse‐related molecules, synaptic structure, and individual behavior

Xiao

Ran

et al. 2023

The FASEB Journal

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Nectin-like family members (Necls) are involved in synaptic organization. In contrast to that of Necl-2/CADM1/SynCAM1, which is critical in synaptic events, investigation of Necl-4/CADM4/SynCAM4 in synapses has largely lagged behind given the particularity of homophilic self-interactions compared to interactions with other Necls. We sought to further understand the role of Necl-4 in synapses and found that knockout of Necl-4 led to aberrant expression levels of proteins mediating synaptic function in cortex homogenates and augmented accumulation of ionotropic glutamate receptor in postsynaptic density fractions, although a compensatory effect of Necl-1 on the expression levels existed. Concurrently, we also found increased synaptic clefts in the cortex and simplified dendritic morphology of primary cultured cortical neurons. Experiments on individual behaviors suggested that compared to their wild-type littermates, Necl-4-KO mice exhibited impaired acquisition of spatial memory and working memory and

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Nectins and Nectin-like molecules in synapse formation and involvement in neurological diseases

Cited by 15 publications

References 115 publications

Necl2/3-mediated mechanism for tripartite synapse formation

Necl2/3-mediated mechanism for tripartite synapse formation

Optochemical profiling of receptor-proximal proteins in vivo in minutes

Indispensable role of Nectin‐like 4 in regulating synapse‐related molecules, synaptic structure, and individual behavior

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