Deorphanizing FAM19A proteins as pan-neurexin ligands with an unusual biosynthetic binding mechanism

Khalaj, Anna J.; Sterky, Fredrik; Sclip, Alessandra; Schwenk, Jochen M.; Brunger, Axel T.; Fakler, Bernd; Südhof, Thomas C.

doi:10.1083/jcb.202004164

Cited by 31 publications

(56 citation statements)

References 58 publications

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“…Consistent with this conclusion, Nrxn1 ligands that appear to block the heparan sulfate modification of neurexins (i.e. CA10 58 and FAM19A1-4 59 ) are not expressed at appreciable levels in astrocytes (Extended Data Fig. 5g).…”

Section: Astrocytic Nrxn1 Forms Contacts With Both Neurons and Blood Vesselssupporting

confidence: 62%

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Trotter

Dargaei

Sclip

et al. 2020

Preprint

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At tripartite synapses, astrocytes surround synaptic contacts, but how astrocytes contribute to the assembly and function of synapses remains unclear. Here we show that neurexin-1α, a presynaptic adhesion molecule that controls synapse properties, is also abundantly expressed by astrocytes. Strikingly, astrocytic neurexin-1α, but not neuronal neurexin-1α, is highly modified by heparan sulfate. Moreover, astrocytic neurexin-1α is uniquely alternatively spliced and invariably contains an insert in splice-site #4, thereby restricting the range of ligands to which it binds. Deletion of neurexin-1 from astrocytes or neurons does not alter synapse numbers or synapse ultrastructure, but differentially impairs synapse function. At hippocampal Schaffer-collateral synapses, neuronal neurexin-1 is essential for normal NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 is required for normal AMPA-receptor-mediated synaptic responses and for long-term potentiation of these responses. Thus, astrocytes directly shape synapse properties via a neurexin-1-dependent mechanism that involves a specific molecular program distinct from that of neuronal neurexin-1.

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Section: Astrocytic Nrxn1 Forms Contacts With Both Neurons and Blood Vesselssupporting

confidence: 62%

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Trotter

Dargaei

Sclip

et al. 2020

Preprint

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“…FAM19A1 is a secreted protein expressed by specific subset of neurons located within several brain areas [24]. It has been demonstrated that FAM19A1 mediates posttranslational modification of neurexins, a family of presynaptic adhesion molecules involved in synaptic function [27]. In addition, ablation of FAM19A1 in mice led to several behavior abnormalities related to aberrant synaptic activities [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…In Fam19a1 knock-out (KO) studies, behaviors of FAM19A1-ablated mice were characterized with hyperactive locomotor activity, longterm memory deficits, fear acquisition failure and feeding behavior abnormalities [24,25]. Moreover, recent studies have shown that FAM19A1 is an active participant in several neurophysiological functions and stimulates its binding partners, G protein-coupled receptor 1 (GPR1) and neurexins (NRXNs) [26,27]. It has been suggested that FAM19A1 could act as a pan-NRXN ligand providing functional diversification to NRXNs, presynaptic membrane-bound proteins that modulate synaptic activities [27].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, recent studies have shown that FAM19A1 is an active participant in several neurophysiological functions and stimulates its binding partners, G protein-coupled receptor 1 (GPR1) and neurexins (NRXNs) [26,27]. It has been suggested that FAM19A1 could act as a pan-NRXN ligand providing functional diversification to NRXNs, presynaptic membrane-bound proteins that modulate synaptic activities [27]. Some behavioral abnormalities shown in Fam19a1 KO mice are occasionally accompanied by unusual synaptic activity [28].…”

Section: Introductionmentioning

confidence: 99%

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Alterations in Dendritic Spine Maturation and Neurite Development Mediated by FAM19A1

Yong

Hwang

Seong

2021

Cells

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Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family with sequence similarity 19 A1 (FAM19A1) is a secreted protein primarily expressed in subsets of terminally differentiated neuronal precursor cells and fully mature neurons in specific brain substructures. Several recent studies have demonstrated the importance of FAM19A1 in brain physiology; however, additional information is needed to support its role in neuronal maturation and function. In this study, dendritic spine morphology in Fam19a1-ablated mice and neurite development during in vitro neurogenesis were examined to understand the putative role of FAM19A1 in neural integrity. Adult Fam19a1-deficient mice showed low dendritic spine density and maturity with reduced dendrite complexity compared to wild-type (WT) littermates. To further explore the effect of FAM19A1 on neuronal maturation, the neurite outgrowth pattern in primary neurons was analyzed in vitro with and without FAM19A1. In response to FAM19A1, WT primary neurons showed reduced neurite complexity, whereas Fam19a1-decifient primary neurons exhibited increased neurite arborization, which was reversed by supplementation with recombinant FAM19A1. Together, these findings suggest that FAM19A1 participates in dendritic spine development and neurite arborization.

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“… Khalaj et al (2020) identified FAM19A, an “orphan” cytokine, as Nrx-binding protein from adult mouse brain. FAM19As bound with Nrxs through intermolecular disulfide bonds that were formed during intracellular transport.…”

Section: Functions Of Vertebrate Glypicans At Synapsesmentioning

confidence: 99%

Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders

Kamimura

Maeda

2021

Front. Neural Circuits

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Heparan sulfate proteoglycans (HSPGs) are components of the cell surface and extracellular matrix, which bear long polysaccharides called heparan sulfate (HS) attached to the core proteins. HSPGs interact with a variety of ligand proteins through the HS chains, and mutations in HSPG-related genes influence many biological processes and cause various diseases. In particular, recent findings from vertebrate and invertebrate studies have raised the importance of glycosylphosphatidylinositol-anchored HSPGs, glypicans, as central players in the development and functions of synapses. Glypicans are important components of the synapse-organizing protein complexes and serve as ligands for leucine-rich repeat transmembrane neuronal proteins (LRRTMs), leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (RPTPs), and G-protein-coupled receptor 158 (GPR158), regulating synapse formation. Many of these interactions are mediated by the HS chains of glypicans. Neurexins (Nrxs) are also synthesized as HSPGs and bind to some ligands in common with glypicans through HS chains. Therefore, glypicans and Nrxs may act competitively at the synapses. Furthermore, glypicans regulate the postsynaptic expression levels of ionotropic glutamate receptors, controlling the electrophysiological properties and non-canonical BMP signaling of synapses. Dysfunctions of glypicans lead to failures in neuronal network formation, malfunction of synapses, and abnormal behaviors that are characteristic of neurodevelopmental disorders. Recent human genetics revealed that glypicans and HS are associated with autism spectrum disorder, neuroticism, and schizophrenia. In this review, we introduce the studies showing the roles of glypicans and HS in synapse formation, neural plasticity, and neurological disorders, especially focusing on the mouse and Drosophila as potential models for human diseases.

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Deorphanizing FAM19A proteins as pan-neurexin ligands with an unusual biosynthetic binding mechanism

Cited by 31 publications

References 58 publications

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Alterations in Dendritic Spine Maturation and Neurite Development Mediated by FAM19A1

Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders

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