RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Wang, Jie; Miao, Yi; Wicklein, Rebecca; Sun, Zijun; Wang, Jinzhao; Jude, Kevin; Fernandes, Ricardo A.; Merrill, Sean; Wernig, Marius; García, K. Christopher; Südhof, Thomas C.

doi:10.1016/j.cell.2021.10.016

Cited by 62 publications

(52 citation statements)

References 92 publications

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“…However, the early expression of NgRs and their ligands in the embryonic nervous system suggested a role of these receptors during development. These suggestions are supported by a recent study demonstrating a role of NgRs in synapse formation in cultured human neurons derived from embryonic stem cells ( J. Wang et al, 2021 ). NgRs bind to brain-specific angiogenesis inhibitors from either glia or neurons to regulate axon elongation or dendritic arborization and synapse formation, respectively.…”

Section: Discussionsupporting

confidence: 57%

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

Vaccaro

Dumoulin²,

Zuñiga³

et al. 2022

J. Neurosci.

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Nogo-66 receptors (NgR1-3) are glycosylphosphatidyl inositol-linked proteins that belong to the leucine-rich repeat superfamily. Through binding to myelin-associated inhibitors, NgRs contribute to the inhibition of axonal regeneration after spinal cord injury. Their role in limiting synaptic plasticity and axonal outgrowth in the adult CNS has been described previously, but not much is known about their role during the development of the nervous system. Here, we show that NgR1 and NgR3 mRNAs are expressed during spinal cord development of the chicken embryo. In particular, they are expressed in the dI1 subpopulation of commissural neurons during the time when their axons navigate toward and across the floorplate, the ventral midline of the spinal cord. To assess a potential role of NgR1 and NgR3 in axon guidance, we downregulated them using in ovo RNAi and analyzed the trajectory of commissural axons by tracing them in open-book preparations of spinal cords. Our results show that loss of either NgR1 or NgR3 causes axons to stall in the midline area and to interfere with the rostral turn of postcrossing axons. In addition, we also show that NgR1, but not NgR3, requires neuronal PlexinA2 for the regulation of commissural axon guidance. SIGNIFICANCE STATEMENT Over the last decades, many studies have focused on the role of NgRs, particularly NgR1, in axonal regeneration in the injured adult CNS. Here, we show a physiological role of NgRs in guiding commissural axons during early development of the chicken spinal cord in vivo . Both NgR1 and NgR3 are required for midline crossing and subsequent turning of postcrossing axons into the longitudinal axis of the spinal cord. NgR1, but not NgR3, forms a receptor complex with PlexinA2 during axon guidance. Overall, these findings provide a link between neural regenerative mechanisms and developmental processes.

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Section: Discussionsupporting

confidence: 57%

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

Vaccaro

Dumoulin²,

Zuñiga³

et al. 2022

J. Neurosci.

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“…Several studies have revealed that tryptophan C-mannosylation enhances the expression of proteins with a TSR domain: it stabilises the fold of these proteins to enable their secretion to the cell surface in metazoans 7 – 10 and the Apicomplexan parasite Toxoplasma 11 . C-mannosylation can also play a role in TSR domain function 4 , 8 , 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission

et al. 2022

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Tryptophan C-mannosylation stabilizes proteins bearing a thrombospondin repeat (TSR) domain in metazoans. Here we show that Plasmodium falciparum expresses a DPY19 tryptophan C-mannosyltransferase in the endoplasmic reticulum and that DPY19-deficiency abolishes C-glycosylation, destabilizes members of the TRAP adhesin family and inhibits transmission to mosquitoes. Imaging P. falciparum gametogenesis in its entirety in four dimensions using lattice light-sheet microscopy reveals defects in ΔDPY19 gametocyte egress and exflagellation. While egress is diminished, ΔDPY19 microgametes still fertilize macrogametes, forming ookinetes, but these are abrogated for mosquito infection. The gametogenesis defects correspond with destabilization of MTRAP, which we show is C-mannosylated in P. falciparum, and the ookinete defect is concordant with defective CTRP secretion on the ΔDPY19 background. Genetic complementation of DPY19 restores ookinete infectivity, sporozoite production and C-mannosylation activity. Therefore, tryptophan C-mannosylation by DPY19 ensures TSR protein quality control at two lifecycle stages for successful transmission of the human malaria parasite.

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“…Indeed, C1QL2 and C1QL3 can bind to neurexin 3 ( Matsuda et al, 2016 ) and a very recent study suggests the formation of a tripartite complex between neuronal pentraxin-1, C1QL3 and BAI3 ( Sticco et al, 2021 ). Very recently, BAI1 and BAI3 receptors were shown to promote synapse formation via transsynaptic binding of RTN4 receptors ( Wang et al, 2021 ). One of the TSP-1 domains in BAI receptors, and its glycosylation, is essential for this binding ( Wang et al, 2021 ), highlighting the importance of TSP-1 domains for synapse formation.…”

Section: Conservation and Extension Of Ancient Functions In Central S...mentioning

confidence: 99%

“…Very recently, BAI1 and BAI3 receptors were shown to promote synapse formation via transsynaptic binding of RTN4 receptors ( Wang et al, 2021 ). One of the TSP-1 domains in BAI receptors, and its glycosylation, is essential for this binding ( Wang et al, 2021 ), highlighting the importance of TSP-1 domains for synapse formation.…”

Section: Conservation and Extension Of Ancient Functions In Central S...mentioning

confidence: 99%

Synapse Formation and Function Across Species: Ancient Roles for CCP, CUB, and TSP-1 Structural Domains

et al. 2022

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The appearance of synapses was a crucial step in the creation of the variety of nervous systems that are found in the animal kingdom. With increased complexity of the organisms came a greater number of synaptic proteins. In this review we describe synaptic proteins that contain the structural domains CUB, CCP, or TSP-1. These domains are found in invertebrates and vertebrates, and CUB and CCP domains were initially described in proteins belonging to the complement system of innate immunity. Interestingly, they are found in synapses of the nematode C. elegans, which does not have a complement system, suggesting an ancient function. Comparison of the roles of CUB-, CCP-, and TSP-1 containing synaptic proteins in various species shows that in more complex nervous systems, these structural domains are combined with other domains and that there is partial conservation of their function. These three domains are thus basic building blocks of the synaptic architecture. Further studies of structural domains characteristic of synaptic proteins in invertebrates such as C. elegans and comparison of their role in mammals will help identify other conserved synaptic molecular building blocks. Furthermore, this type of functional comparison across species will also identify structural domains added during evolution in correlation with increased complexity, shedding light on mechanisms underlying cognition and brain diseases.

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RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Cited by 62 publications

References 92 publications

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission

Synapse Formation and Function Across Species: Ancient Roles for CCP, CUB, and TSP-1 Structural Domains

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