Planar cell polarity protein Celsr2 maintains structural and functional integrity of adult cortical synapses

Li, Cunzheng; Wei, Ji‐an; Wang, Diyang; Luo, Zundu; Pang, Chaoqin; Chen, Kai; Duan, Juan; Chen, Bailing; Zhou, Libing; Tissir, Fadel; Shi, Lei; So, Kwok‐Fai; Zhang, Li; Qu, Yibo

doi:10.1016/j.pneurobio.2022.102352

Cited by 5 publications

(10 citation statements)

References 36 publications

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“…Similar extent of reduction of synapses was seen in the cerebellum of the Celsr3 conditional knockout mice from postnatal day 10 11 . The fact that the PCP proteins also regulate the stability and number of glutamatergic synapses in adulthood is fascinating and important 9,10,12,13 . Furthermore, PCP proteins appear to regulate synaptic plasticity 11,13,29 .…”

Section: Discussionmentioning

confidence: 72%

“…11 The fact that the PCP proteins also regulate the stability and number of glutamatergic synapses in adulthood is fascinating and important. 9,10,12,13 Furthermore, PCP proteins appear to regulate synaptic plasticity. 11,13,29 A regulator of PCP signaling, Lgl1, also regulates synapse numbers in development and in adulthood as well as synaptic plasticity in adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggest that the components of the signaling pathway for planar cell polarity (PCP), the global cell and tissue polarity along the tissue plane, are key regulators of glutamatergic synapse formation and maintenance in the developing and mature neural circuits and the PCP pathway may be a candidate for a common pathway for the assembly of the vast majority of glutamatergic synapses. [8][9][10][11][12][13][14][15][16]…”

mentioning

confidence: 99%

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Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

Freitas

Gorodetski

Lim

et al. 2023

Developmental Dynamics

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The local signaling mechanism which directly assembles and maintains glutamatergic synapses has not been well understood. Glutamatergic synapses are made of presynaptic and postsynaptic compartments with distinct sets of proteins. The planar cell polarity (PCP) pathway is highly conserved and responsible for establishing and maintaining the cell and tissue polarity along the tissue plane. The six core PCP proteins form antagonizing complexes within the cells and asymmetric intercellular complexes across neighboring cells which regulate cell‐cell interactions during planar polarity signaling. Accumulating evidence suggests that the PCP proteins play essential roles in glutamatergic synapse assembly, maintenance and function in the brain. This review summarizes the key evidence that PCP proteins may be responsible for the formation and stability of the vast majority of the glutamatergic synapses in hippocampus and medial prefrontal cortex, the progress in understanding the mechanisms of how PCP proteins assemble and maintain glutamatergic synapses and initial insights on how disruption of the function of the PCP proteins can lead to neurodegenerative, neurodevelopmental and neuropsychiatric disorders. The PCP proteins may be the missing pieces of a long‐standing puzzle and filling this gap of knowledge may provide the basis for understanding many unsolved questions in synapse biology.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

Freitas

Gorodetski

Lim

et al. 2023

Developmental Dynamics

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“…Given the differences in results with distinct mouse lines and the possibility of major genetic background effects, a more reductionist approach may be needed to deconstruct the contribution of latrophilins in general and Lphn1 in particular to different types of synapses. For example, it is possible that latrophilins function in the same pathway as other aGPCRs, such as BAI's and CELSRs that also have synaptic functions (Najarro et al 2012, Sigoillot et al 2015, Wang et al 2020, Wang et al 2021, Bolliger et al 2011, Shiu et al 2022, Tu et al 2018, Zhu et al 2015, Stephenson et al 2013, Aimi et al 2023, Martinelli et al 2016, Kakegawa et al 2015, Freitas et al 2023, Li et al 2022, Zhou et al 2021, Thakar et al 2017, and that a more extensive deletion of multiple genes will be necessary to unravel the making of a synapse! into 75 cm 2 of 40-50% confluent HEK293T culture using a calcium-phosphate approach.…”

Section: Discussionmentioning

confidence: 99%

“…This domain combination places aGPCRs at the intersection of cell-cell or cell-matrix adhesion and signal transduction, although the precise functions of most aGPCRs are unclear. Multiple aGPCRs, including brain angiogenesis inhibitors (BAI’s), latrophilins, and CELSR’s, are thought to contribute to synapse formation (Najarro et al 2012, Sigoillot et al 2015, Wang et al 2021, Wang et al 2020, Bolliger et al 2011, Shiu et al 2022, Tu et al 2018, Zhu et al 2015, Stephenson et al 2013, Aimi et al 2023, Martinelli et al 2016, Kakegawa et al 2015, Freitas et al 2023, Li et al 2022, Zhou et al 2021, Thakar et al 2017, Anderson et al 2017, Sando et al 2019), although limited information is available about their mechanisms of action and scope of functions.…”

Section: Introductionmentioning

confidence: 99%

The Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses

Matúš,

Lopez,

Sando

et al. 2023

Preprint

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Latrophilin-1 (Lphn1, a.k.a. CIRL1 and CL1; gene symbolAdgrl1) is an Adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knockin/knockout mice for Lphn1 that contain an extracellular myc-epitope tag. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but contributes to inhibitory synaptic connections.

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Exonic mutations in cell–cell adhesion may contribute to CADASIL-related CSVD pathology

et al. 2023

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15–23% of individuals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 individuals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell–cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF < 0.001) and predicted functionally relevant (SIFT < 0.05, PolyPhen > 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF, GPR17, PTPRS, and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease.

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Planar cell polarity protein Celsr2 maintains structural and functional integrity of adult cortical synapses

Cited by 5 publications

References 36 publications

Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

The Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses

Exonic mutations in cell–cell adhesion may contribute to CADASIL-related CSVD pathology

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