
==== Front
Glycobiology
Glycobiology
glycob
Glycobiology
0959-6658
1460-2423
Oxford University Press

10.1093/glycob/cwae051
cwae051
Review
AcademicSubjects/SCI01000
Dystroglycan-HSPG interactions provide synaptic plasticity and specificity
https://orcid.org/0000-0001-9237-0524
Melrose James Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, St. Leonards, NSW 2065, Australia
School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia

Corresponding author: Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Level 10, Kolling Institute of Medical Research, B6, The Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. Email: james.melrose@sydney.edu.au
10 2024
02 9 2024
02 9 2024
34 10 cwae05114 6 2024
14 6 2024
10 7 2024
02 9 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Aim: This study examined the roles of the laminin and proteoglycan receptor dystroglycan (DG) in extracellular matrix stabilization and cellular mechanosensory processes conveyed through communication between the extracellular matrix (ECM) and cytoskeleton facilitated by DG. Specific functional attributes of HS-proteoglycans (HSPGs) are conveyed through interactions with DG and provide synaptic specificity through diverse interactions with an extensive range of cell attachment and adaptor proteins which convey synaptic plasticity. HSPG-DG interactions are important in phototransduction and neurotransduction and facilitate retinal bipolar-photoreceptor neuronal signaling in vision. Besides synaptic stabilization, HSPG-DG interactions also stabilize basement membranes and the ECM and have specific roles in the assembly and function of the neuromuscular junction. This provides neuromuscular control of muscle systems that control conscious body movement as well as essential autonomic control of diaphragm, intercostal and abdominal muscles and muscle systems in the face, mouth and pharynx which assist in breathing processes. DG is thus a multifunctional cell regulatory glycoprotein receptor and regulates a diverse range of biological and physiological processes throughout the human body. The unique glycosylation of the αDG domain is responsible for its diverse interactions with ECM components in cell-ECM signaling. Cytoskeletal cell regulatory switches assembled by the βDG domain in its role as a nuclear scaffolding protein respond to such ECM cues to regulate cellular behavior and tissue homeostasis thus DG has fascinating and diverse roles in health and disease.

cell-extracellular matrix communication
dystroglycan
heparan sulphate proteoglycans
neurotransmission
phototransmission
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pmcIntroduction

Dystroglycan (DG) is a multifunctional cell adhesion laminin receptor composed of covalently linked α extracellular and cytoplasmic β domains that act not only as an anchorage for cells to the ECM but it also modulates outside-in cell signaling (Bello and Darribère 2016). αDG is a ubiquitous neural receptor in skeletal muscle, CNS/PNS, digestive tract, kidney, skin and reproductive system binding to laminins, agrin and perlecan in muscle and brain ECM and with slit proteins in the spinal cord, neurexin in synapses and pikachurin in the retina (Marrone et al. 2011; Nickolls and Bönnemann 2018; Lindenmaier et al. 2019; Jahncke and Wright 2023; Sciandra et al. 2023). Interaction of αDG with HSPGs conveys some of its key functional attributes (Gee et al. 1994; Jacobson et al. 2001; Jahncke and Wright 2023). αDG is a heavily glycosylated protein with glycan representing over 50% of its mass however brain αDG has reduced glycosylation and ligand binding affinity compared to muscle αDG reflecting differing tissue-specific functional duties. αDG interaction with agrin and perlecan supports the localization of acetylcholinesterase and acetylcholinesterase receptors in motor neurons which regulate conscious and autocrine neuromuscular activity (Gee et al. 1994; Jacobson et al. 2001; Saito et al. 2003). The α-domain of DG has unique glycosylation patterns that facilitate interaction with ECM components (Briggs et al. 2016). DG has a unique sugar composition including the presence of two ribitol phosphates on the matriglycan component of DG (Manya et al. 2016). The muscular dystrophy gene to a trans-membrane protein (TMEM) encodes a ribitol-β1,4-xylosyl transferase biosynthetic enzyme responsible for attachment of the Xylβ1-4Rbo5P disaccharide to the O-mannosyl linkage region and is also responsible for the elongation of the 3GlcAβ1-3Xylα1- units on the mannosyl chain (Praissman et al. 2016; Okuma et al. 2023). Thus TMEM5 acts as a UDP-D-xylose:ribitol-5-phosphate β1,4-xylosyltransferase. This provides an essential aspect of the functional glycosylation of DG in health and disease (Goddeeris et al. 2013). The glucuronyl-transferase B4GAT1 is required for initiation of LARGE-mediated αDG functional glycosylation (Praissman et al. 2014; Willer et al. 2014).

αDG interacts with agrin, neurexin, perlecan, eyes-shut and pikachurin (Ibraghimov-Beskrovnaya et al. 1992; Gee et al. 1994; Sugita et al. 2001; Sato et al. 2008) in neural and ocular tissues conveying synaptic stabilization, synaptic plasticity and specificity of action. The cytoplasmic β-domain of DG interacts with adaptor and cytoskeletal proteins such as ezrin that regulate cytoskeletal organization acting as molecular switches for the transmission of ECM to the cell (Sciandra et al. 2023) regulating cell signaling through the cytoskeletal protein dystrophin (Ibraghimov-Beskrovnaya et al. 1992; Suzuki et al. 1994; Jung et al. 1995).

Dystroglycan and mechanotransduction

The dystrophin-glycoprotein complex has a central role to play in mechanotransduction (Campbell and Kahl 1989). DG complexes with dystrophin, sarcoglycan-sarcospan and syntrophin to facilitate mechanotransductive processes (Fig. 1). Mechano-transducer accessory proteins such as neuronal nitric oxide synthase (Garbincius and Michele 2015) and YAP also attach to dystrophin, a PPxY binding motif sequesters YAP (McNally et al. 1998; Garbincius and Michele 2015; Morikawa et al. 2017). Dystrophin also regulates mechanosensitive ion channels including stretch-activated Ca2+ channels and transient receptor potential cation (TRPC) channels (Millay et al. 2009). Cyclic stretch activates ERK1/2 and 5′ cyclic monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways via the DG glycoprotein complex and an associated protein, plectin which forms a mechanotransductive scaffold in conjunction with DG (Takawira et al. 2011; Winter and Wiche 2013).

Fig. 1 Schematic depiction of the structural organization of the dystroglycan laminin receptor showing it’s covalently linked α and β domains, extensive glycosylation of the α-domain, and sarcospan, sarcoglycan glycoproteins and stretch receptors that interact with the αDG domain. βDG interactive cytoplasmic proteins including dystrophin, plectin, dystrobrevin, syntrophin form an organizational instructive scaffold of importance in cell signaling. This scaffold interfaces with the actin cytoskeleton which transfers cyclic stretching and relaxation that regulates extracellular signal-regulated kinase 1/2 (ERK1/2) cell signaling. An influx of Ca2+ through stretch activated ion-channels regulate neuronal nitric oxide synthase (nNOS) activity, a signaling molecule that provides synaptic plasticity. This also regulates the cerebrovasculature of the neurovascular unit in the CNS/PNS and regulates brain perfusion. Plectin has actin, dystrophin, integrin and βDG binding sites and forms an interactive instructional scaffold with important roles in cell-signaling. βDG also has a binding site for yes associated protein (YAP), a transcription factor effector of the hippo cell signaling pathway. This is a mechanosensitive cell signaling pathway that regulates tissue composition, aids in the homeostasis of tissues and also regulates the final size attained by organs in maturity.

βDG interactome

βDG has roles as a nuclear scaffolding protein (Sciandra et al. 2024) and is localized with MEK (mitogen activated protein kinase) in membrane ruffles and with ERK (Extracellular signal-regulated kinase) in focal adhesions in fibroblasts. MEK is a serine/tyrosine/threonine kinase that phosphorylates and activates MAPK (mitogen-activated protein kinase) while ERK is a serine/threonine-specific protein kinase, ERK signaling represents the culmination of the MAPK cascade. ERK/MAPK signaling is essential in the development of the nervous system from neuroprogenitor cell populations (Iroegbu et al. 2021). Interaction of βDG with ezrin regulates cytoskeletal organization (Iroegbu et al. 2021) (Fig. 2). The long arm of laminin contains five homologous A chain LamG domains that interact with integrins α6β1 (Aumailley et al. 1990), α7β1 (Kramer et al. 1991), and α3β1 (Gehlsen et al. 1992) and HS in ECM and cell surface HSPGs (Yurchenco et al. 1990). The dystrophin scaffold interacts with stretch receptors regulating ion channels and the influx of Ca2+ into the neuron. Ca 2+ is a universal second messenger in neurons regulating membrane depolarization and neuronal activation. Neuronal nitric oxide synthase (nNOS) also binds to the dystrophin-actin cytoskeletal scaffold and regulates the cerebral vasculature (Melikian et al. 2009; Förstermann and Sessa 2012; Costa et al. 2016) and regulates the perfusion of the brain (O'Gallagher et al. 2022). Cyclic stretching conveyed through the actin cytoskeleton regulates ERK1/2 signaling (Wortzel and Seger 2011).

Fig. 2 Schematic depiction of the DG laminin receptor and some of its interactive ligands. Some of the extracellular HSPG ligands that interact with αDG are shown including, perlecan, agrin, pikachurin and eyes-shut. Biosynthetic enzymes responsible for the glycosylation of the α-dystroglycan matriglycan component are also shown emphasizing the unique glycosylation of DG which conveys its unique interactive properties with ECM components.

Glycosyl sulfotransferases modulate bioresponsive HSPG regulatory properties

Spatio-temporal glycosylation patterns of ECM components drive developmental processes and maintain tissue homeostasis (Basu et al. 2022) in health and disease (Reily et al. 2019) emphasizing the significant roles of glycosyltransferases in the determination of tissue form and function (Mehboob and Lang 2021). The link between the unique glycosylation patterns of DG and muscular dystrophies is a good example of how aberrant glycosylation of key ECM effector molecules can effect normal tissue function. HS synthesis in tissues is complex and gives rise to side chains in HSPGs that vary in sequence and sulfation patterns providing an extraordinary diversity in the ligand interactive capability of HSPGs in the glycocalyx and ECM (Cummings 2009). Spatio-temporally expressed glycosylation patterns (Basu et al. 2022) drive tissue morphogenesis and also maintain tissue homeostasis and function (Reily et al. 2019) emphasizing the modulatory roles of glycosyltransferases in normal and pathological tissues (Nogami et al. 2004). Subtle control of HS structure can modulate biological responses in-situ (Bishop et al. 2007; Basu et al. 2022) through interactions with structural ECM proteins, cell adhesive glycoproteins, integrins, receptors (Gopal et al. 2021) and chemokines (Gordts and Esko 2015).

Dystroglycan-HSPG interactions of importance in vision

DG has roles in the development and function of the nervous system (Jahncke and Wright 2023) and affects the structural remodeling of dendritic spines (Figiel et al. 2022). Pikachurin, synthesised by photoreceptors, forms a key post-synaptic DG signaling complex downstream of ON-bipolar neurons (Orlandi et al. 2018) and regulates functional synaptic connection between retinal photoreceptor and bipolar cells (Omori et al. 2012). Pikachurin also has roles in the formation and stabilization of the photoreceptor ribbon synapse through interaction with DG. Furthermore, LRRTM synaptic adhesion molecules also have roles in retinal synapse formation, signaling specificity and stabilization through interactions with HSPGs. LRRTM4 is enriched in retinal rod bipolar cells which connect with rod photoreceptors to facilitate neurotransmission and phototransductive processes in vision (Agosto and Wensel 2021). To date, only one highly conserved DG gene has been discovered in mammals (Henry and Campbell 1999). DG has many roles in CNS/PNS neural circuit development (Jahncke and Wright 2023) α is a peripheral membrane lectin-like glycoprotein, with an abundance of O-linked glycan in its αDG extracellular domain while the membrane-spanning β-DG domain organizes cytoskeletal proteins with roles in cell signaling (Ervasti and Campbell 1991). The mucin-rich region of α-DG is rich in serine and threonine residues substituted with ~40 O-Man and O-GalNAc residues (Gomez Toledo et al. 2012; Harrison et al. 2012) and matriglycan (Goddeeris et al. 2013) which may exceed 100 disaccharides in length. These residues interact with LamG domains in HSPGs (Hohenester 2019) linking αDG to the basement membrane (Yoshida-Moriguchi and Campbell 2015) and also aid in the stabilization of the photoreceptor ribbon synapse and ciliary axenome through interactions mediated by eyes-shut and pikachurin.

Eyes shut and Pikachurin

Human Eyes shut (EYS), contains five LamG domains, three of these are predicted to be functional Ca2+ binding sites (Yu et al. 2016; Lu et al. 2017). Mutations in EYS result in retinitis pigmentosa demonstrating the important roles it plays in vision (Abd el-Aziz et al. 2008, Collin et al. 2008). Over 100 unique missense variants have been detected, two of these affect a putative Ca2+ ligand binding site in LamG4. The interaction of pikachurin with α-DG provides synaptic stabilization between retinal photoreceptor and bipolar neurons essential for the processing of phototransductive and neurotransductive ocular signals and ocular vision (Sato et al. 2008). Pikachurin interacts with dystrophin-DG complexes, and GPR179 orphan receptor in bipolar neurons to facilitate phototransduction and neurotransduction of ocular signals to the brain (Fig. 3). GPR179 is specifically expressed in the retina, it forms complexes in native retinas with mGluR6 (metabotropic glutamate receptor 6) and TRPM1 (transient receptor potential cation channel subfamily M member 1), the main components of the signaling in ON-bipolar cells (ON-BC) to regulate G protein-coupled receptor (GPCR) signaling. ON-BCs are involved in spatial processing of the visual inputs from photoreceptors (Koike et al. 2010; Orlandi et al. 2012). Photoreceptor activation in response to light exposure results in an influx of Ca2+ through a CAV1.4 voltage gated calcium channel. This initiates synaptic vesicle mobilization and migration to the synaptic gap where membrane fusion of the synaptic vesicles releases glutamate neurotransmitter into the synaptic cleft between photoreceptors and ON bipolar cells. Glutamate is taken up by mGluR6 on the ON bipolar neuron initiating a G-protein coupled signaling cascade, mGluR6 and TRPM1 regulate this neurotransductive response (Kolb et al. 1995; Martemyanov and Sampath 2017), TRPM1 is enriched in ON bipolar neurons, GPR179 orphan receptor, is specifically expressed in retinal neurons and forms a complex with mGluR6 and TRPM1 regulating these interactions (Nomura et al. 1994; Koike et al. 2010; Morgans et al. 2010) and is also a ligand for pikachurin which in turn interacts with αDG to stabilise the ribbon synapse. The LG2-EGF-EGF-LG3 domains of pikachurin are responsible for its α-DG binding activity (Kanagawa et al. 2010). This interaction stabilizes the axonome primary cilium which attaches outer regions of photoreceptors and their inner regions.

Fig. 3 Schematic depiction of pikachurin interaction with dystroglycan and dystrophin in the photoreceptor ribbon synapse, GPR 158/179 orphan receptor and mGluR6 in neurotransduction with retinal bipolar neurons in visual processing. 1. Photons are captured as part of the phototransductive process which 2. Activates the voltage gated CAV1.4 Ca2+ channel. 3. The influx of Ca2+ activates transport processes of Glu neurotransmitter within synaptic vesicles which merge with the membrane of the synaptic gap. 4. This results in the release of glutamate into the synaptic gap. 5. Glutamate is taken up by the mGluR6 metabromic glutamate receptor on bipolar neurons in the retina. 6. Transient receptor potential cation channel subfamily M member 1 (TRPM1) regulates neurotransduction in activated bipolar neurons as part of visual processing. ON-bipolar cell dendrites express a unique metabotropic glutamate receptor 6 (mGluR6). TRPM1 is a mGluR6-coupled cation channel in retinal ON-bipolar cells that regulates G protein receptor (GPCR) coupled signaling. TRPMI1 is the end-point of the mGluR6 signal transduction cascade in bipolar neurons in the retina.

Neurexins provide synaptic stability, plasticity and specificity of interaction in neurotransduction and network signaling

Neurexins are key organizers of synapses that perform specific functions that are essential for normal brain function (Reissner et al. 2013) and are presynaptic cell-adhesion receptors that occur as two principal forms, a longer α-neurexin and a shorter β-neurexin. α-Neurexin core proteins contain six Laminin G LNS (laminin/neurexin/sex-specific globulin) domains, these are interspersed with three EGF-like domains, an O-linked carbohydrate attachment region, and a cysteine-loop domain (Liu et al. 2018). α-neurexins, also contain a transmembrane region and a short cytoplasmic tail. β-Neurexins contain a short N-terminal β-neurexin-specific sequence spliced on to an α-neurexin LamG domain. Vertebrate neurexins undergo extensive alternative splicing producing thousands of isoforms (Ullrich et al. 1995; Treutlein et al. 2014), interactive with a vast range of binding partners through vast epitope coverage (Chowdhury et al. 2021). Examples of binding partners for the neurexins include the calcium/calmodulin-dependent serine protein kinase (CASK) (Stevenson et al. 2000; Hsueh 2006; LaConte et al. 2016; Pan et al. 2021; Dybus et al. 2023), the leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) (Lee et al. 2020), the neuroligins (Lisé and El-Husseini 2006; Bourne and Marchot 2014; Qin et al. 2020) and leucine-rich-repeat transmembrane neuronal proteins (LRRTMs) (Roppongi et al. 2017) and MINT proteins (Chatr-aryamontri et al. 2007; Ceol et al. 2010). MINTS regulate APP trafficking and βA generation, deletion of MINTS decreases βA plaque formation in AD models (Ho et al. 2008). MiNT 3 (Mitochondrial inner NEET protein) is an inner mitochondrial Fe-S protein with multiple roles in the regulation of Fe metabolism, free radical and ATP production in health and disease and due to the labile nature of the co-ordination of its two functional Fe-S clusters is a potential therapeutic target (Tamir et al. 2015; Lipper et al. 2018; Mittler et al. 2019; Molino et al. 2020). Many of these interactions with synaptic proteins are mediated by the glycosaminoglycan (GAG) side chains of the neurexins (Yamaguchi 2002; Zhang et al. 2018) and provide synaptic specificity (de Wit and Ghosh 2016; Condomitti and de Wit 2018; Zhang et al. 2018; Melo-Filho et al. 2024) (Fig. 4). Mutations in neurexin genes, in particular NRXN1, are associated with diverse neuropsychiatric disorders (Cuttler et al. 2021). Neurexin KO causes diverse synaptic phenotypes in a synapse-specific manner ranging from effects on synapse numbers to regulation of synaptic Ca2+-signaling and neuronal signal transduction (Chen et al. 2024). AMPAR, (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors), NMDAR, (N-methyl-D-aspartate glutamate receptor) and the GluD2, (Glutamate receptor), ionotropic, delta 2 (Matsuda et al. 2010) contribute to the specificity of synaptic interactions, synaptic plasticity and neurotransmission (Chater and Goda 2014; Royo et al. 2022).

Fig. 4 Schematic depiction of the synapse and proteins that interact with neurexins with roles in synaptic stabilization and which convey diverse interactions that provide synaptic specificity and plasticity in neurotransmission.

Perlecan and Agrin

Binding of perlecan and agrin to α-DG involves multiple LamG domains (Fallon and Hall 1994), (Talts et al. 1999). Perlecan clusters with DG and AChRs on the surface of muscle cells in the NMJ, this interaction is Ca2+ dependant (Andac et al. 1999; Talts et al. 1999). Agrin and perlecan have important roles in the clustering of acetyl cholinesterase receptors and acetyl cholinesterase enzyme in NMJ neuron basal structures interacting with a wide range of structural and cell adhesive glycoproteins such as MusK and CollQ in NMJ assembly and function; Aldunate et al. 2004; Smirnov et al. 2005; Sigoillot et al. 2010; Hubbard and Gnanasambandan 2013; Li et al. 2018; Guarino et al. 2020; Uyen Dao et al. 2023). Perlecan, agrin, type XVIII collagen form stabilizing networks in basement membranes. HSPGs have important instructive roles in neural network development (Melrose et al. 2021) and in neurodegenerative processes (Pintér and Alpár 2022). HSPGs promote deposition in brain tissues of insoluble pathological protein aggregates that contribute to the pathogenesis of diseases of cognitive decline such as AD and PD (Melrose, J., Smith, MM.).

Degradation of the neural ECM by MMPs in neurodegenerative conditions

ECM assembly is altered in schizophrenia and diseases of cognitive decline such as AD and PD (Sethi and Zaia 2017) due to defective assembly processes and excessive catabolism of ECM components by MMPs and ADAMTS metalloproteases. MMPs also have roles in the turnover of ECM components during ECM remodeling in tissue morphogenesis and normal tissue development (Brkic et al. 2015; Rempe et al. 2016) as well as in ECM repair processes. Post translational modification of proteoglycans by MMPs is a normal event in tissue growth and development (Mead et al. 2022). MMP activity is normally controlled by endogenous MMP inhibitory proteins (Gardner and Ghorpade 2003; Lukaszewicz-Zając et al. 2014; Caban et al. 2022) however when this system is dysregulated this can lead to neurodegenerative and psychiatric disorders through defective cellular activity and tissue function (Kim and Joh 2012; Sethi and Zaia 2017; Rivera et al. 2019). An intricate stabilizing network of CNS/PNS proteoglycans functionalize neuronal and astrocyte niche micro-environments in the brain optimizing cellular activity by preserving membrane polarization dynamics, ionic micro-environments, ion fluxes, neuronal activation and network neurotransduction (Melrose 2024). The neuron is an ion sensitive cell type and control of its ionic environment is required to optimise activity in neurotransmission and co-ordination of neural network activity.

Table 1 summarises the functional attributes of some HSPG-DG interactions.

Table 1 Multifunctional HSPGs interactive with dystroglycan.

Protein	Sensory processes affected	Function	
Perlecan	Perlecan is cytoprotective and facilitates cell-ECM osmo-mechanosensory instructive cues properties.	The three LamG domains in domain V of perlecan interact with α-DG. Perlecan regulates diverse cellular processes(Whitelock et al. 2008), stabilises tissues, sequesters growth factors/morphogens, regulates tissue development and morphogenesis, cell proliferation/differentiation in chondrogenesis,vasculogenesis, osteogenesis, inflammation, cardiac development, and angiogenesis (Lord et al. 2014; Vincent et al. 2022). Perlecan has mechanosensory, osmoregulatory roles in weight bearing and tensional connective tissues (Zhao et al. 2020; Guilak et al. 2021) and acts as a shear flow biosensor for endothelial cells and osteocytes, regulates SMCs, vascular tone, blood pressure, bone assembly and homeostasis (Thompson et al. 2011; Wang et al. 2014; Wijeratne et al. 2016). Perlecan is a key component of the vascular ECM and maintains endothelial cell barrier function, it inhibits SMC proliferation and maintains vascular homeostasis. Perlecan has roles in the repair of diseased connective tissues (Arikawa-Hirasawa 2022; Hayes et al. 2022; Hayes and Melrose 2023; Zhao et al. 2023). More than 30 HSPG2 mutations lead to Schwartz-Jampel Syndrome (Lin et al. 2021).	
Collagen XVIII	Assembly and stabilization of basement membranes	Collagen XVIII stabilises NMJ assembly and function, eye development and maintenance of the BBB basement membranes. Collagen XVIII levels are elevated in cerebrospinal fluid following traumatic brain injury (Chen et al. 2013) and associated with brain lesions(Mueller et al. 2007).	
Agrin	Assembly and function of NMJ, regulation of cardiomyocyte function, bioresponsive mechanoreceptor regulated by Hippo cell signaling	Agrin initiates MuSK kinase activity, a receptor tyrosine kinase and a key regulator of NMJ development. Agrin interacts with LRPR, rapsyn and DOK-7 cytoplasmic adaptor protein (Burgess et al. 1999). The NMJ agrin-Lrp4-MuSK cell signaling pathway (Herbst 2020) is disrupted in congenital myasthenia syndromes, Schwartz-Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Impaired MuSK signaling causes severe muscle weakness in congenital myasthenic syndromes. DOK7 promotes NMJ regeneration after nerve injury (Kosco et al. 2023), neuronal agrin promotes myoblast proliferation(Gros et al. 2022). Neuronal LRP4 regulates synapse formation and synaptic plasticity (Karakatsani et al. 2017). Mechanosensitive Yap/Taz effectors of Hippo cell signaling regulate cardiomyocyte replication/regeneration through Agrin.	
α, β, γ Neurexin	Pre/Post Synaptic organization and function	Neurexins have cell adhesive functional interactions with several hundred synaptic proteins providing diversity and specificity in synaptic activity (Dai et al. 2022; Traunmüller et al. 2023). Stabilization of neural pre-and post synaptic terminal interconnections promote neurotransduction efficiency and synaptic plasticity in neural networks (Kim et al. 2022). Neurexin multi-protein complexes regulate pre-synaptic voltage gated Ca channels and functional neuronal receptors (Noborn and Sterky 2023) in health and disease (Cuttler et al. 2021).	
Eyes Shut (Eys)	Photoreceptor stabilization and function	Eyes shut interacts with matriglycan O-mannosyl glycans on α-DG to stabilise the photoreceptor ribbon synapse in phototransductive interactions with retinal bipolar neurons (Husain et al. 2006; Liu et al. 2020), maintain photoreceptor morphology and visual acuity. Mutations in Eys result in vision impairment in retinitis pigmentosa (Suvannaboon et al. 2022).	
Pikachurin	Photoreceptor stabilization and function	Pikachurin stabilises the photoreceptor axoneme cilium and ribbon synapse (Sugita et al. 2015; Furukawa et al. 2020), interacts with orphan receptor GPR179 (Orlandi et al. 2012; Orlandi et al. 2018) and α-DG in phototransduction (Furukawa et al. 2020) involving bipolar neurons of the retinal neural network essential in vision (Sato et al. 2008; Omori et al. 2012; Orlandi et al. 2018; Furukawa et al. 2020). LamG-domains interact with α-DG.	

Conclusions

Dystroglycan is a fascinating multifunctional laminin receptor with important roles in cell-ECM signaling and the regulation of neuronal activity and control of cellular behavior in health and disease. While the major focus of the present review was to explore the role of DG in neural tissues it should be noted that DG also has equally important regulatory roles in many other human tissues. The role of DG in the assembly and function of the NMJ in neuromuscular regulation was also briefly commented on. The importance of DG in this area becomes apparent when DG activity is affected by mutation or trauma and exemplified by a number of muscular dystrophy disorders. Dysfunctional DG activity in so-called dystroglycanopathies are clear examples of DG’s importance in neuromuscular control and when deregulated its impact on conscious human movement. DG also has roles in autonomic co-ordinated control of the diaphragm, intercostal and abdominal muscles as well as muscle systems in the face, mouth and pharynx which all assist in breathing processes. This is but one example of the diverse roles of DG in other human tissues. A greater understanding of the diverse properties of DG is thus clearly relevant to many areas of human physiology and cellular regulation in health and disease.

Acknowledgments

This study was funded by The Melrose Personal Research Fund, Sydney, Australia. JM conceptualized, wrote, edited and revised all versions of the manuscript to final copy.

 

Conflict of interest statement. None declared.

Disclosures

JM has no conflicts to report. JM has received consultancy fees from Arthropharm-Fidia Pharmaceutic Co. Ltd. This company had no input to the writing of this manuscript or the interpretation of the findings or its conclusions or the reason to publish this study.
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References

Abd el-Aziz MM , BarraganI, O'DriscollCA, GoodstadtL, PrigmoreE, BorregoS, MenaM, PierasJI, el-AshryMF, SafiehLA, et al. EYS, encoding an ortholog of drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet. 2008:40 (11 ):1285–1287.18836446
Agosto M , WenselTG. LRRTM4 is a member of the transsynaptic complex between rod photoreceptors and bipolar cells. J Comp Neurol. 2021:529 (1 ):221–233.32390181
Aldunate R , CasarJC, BrandanE, InestrosaNC. Structural and functional organization of synaptic acetylcholinesterase. Brain Res Brain Res Rev. 2004:47 (1-3 ):96–104.15572165
Andac Z , SasakiT, MannK, BrancaccioA, DeutzmannR, TimplR. Analysis of heparin, α-dystroglycan and sulfatide binding to the G domain of the laminin α1 chain by site-directed mutagenesis. J Mol Biol. 1999:287 (2 ):253–264.10080889
Arikawa-Hirasawa E . Impact of the heparan sulfate proteoglycan perlecan on human disease and health. Am J Physiol Cell Physiol. 2022:322 (6 ):C1117–C1122.35417267
Aumailley M , TimplR, SonnenbergA. Antibody to integrin alpha 6 subunit specifically inhibits cell-binding to laminin fragment 8. Exp Cell Res. 1990:188 (1 ):55–60.2139418
Basu A , PatelNG, NicholsonED, WeissRJ. Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease. Am J Physiol Cell Physiol. 2022:322 (5 ):C849–C864.35294848
Bello V , Darribère, T. Dystroglycan. In: ChoiS, editors Encyclopedia of Signaling molecules . New York, NY: Springer; 2016. 10.1007/978-1-4614-6438-9_101578-1.
Bishop J , SchukszM, EskoJD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007:446 (7139 ):1030–1037.17460664
Bourne Y , MarchotP. The neuroligins and their ligands: from structure to function at the synapse. J Mol Neurosci. 2014:53 (3 ):387–396.24497299
Briggs D , Yoshida-MoriguchiT, ZhengT, VenzkeD, AndersonME, StrazzulliA, MoracciM, YuL, HohenesterE, CampbellKP. Structural basis of laminin binding to the LARGE glycans on dystroglycan. Nat Chem Biol. 2016:12 (10 ):810–814.27526028
Brkic M , BalusuS, LibertC, VandenbrouckeRE. Friends or foes: matrix Metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediat Inflamm. 2015:2015 :1–27.
Burgess R , NguyenQT, SonYJ, LichtmanJW, SanesJR. Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. Neuron. 1999:23 (1 ):33–44.10402191
Caban M , OwczarekK, LewandowskaU. The role of Metalloproteinases and their tissue inhibitors on ocular diseases: focusing on potential mechanisms. Int J Mol Sci. 2022:23 (8 ):4256.35457074
Campbell K , KahlSD. Association of dystrophin and an integral membrane glycoprotein. Nature. 1989:338 (6212 ):259–262.2493582
Ceol A , Chatr AryamontriA, LicataL, PelusoD, BrigantiL, PerfettoL, CastagnoliL, CesareniG. MINT, the molecular interaction database: 2009 update. Nucleic Acids Res. 2010:38 (suppl_1 ):D532–D539.19897547
Chater T , GodaY. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Front Cell Neurosci. 2014:8 :401.25505875
Chatr-aryamontri A , CeolA, PalazziLM, NardelliG, SchneiderMV, CastagnoliL, CesareniG. MINT: the molecular INTeraction database. Nucleic Acids Res. 2007:35 (Database ):D572–D574.17135203
Chen H , XueLX, CaoHL, ChenSW, GuoY, GaoWW, JuSM, TianHL. Endostatin/collagen XVIII is increased in cerebrospinal fluid after severe traumatic brain injury. Biomed Res Int. 2013:2013 :402375.24089677
Chen L , JiangM, ZhangB, GokceO, SüdhofTC. Conditional deletion of all Neurexins defines diversity of essential synaptic organizer functions for Neurexins. Neuron. 2024:112 (11 ):1893–00361.38759642
Chowdhury D , WattersK, BiedererT. Synaptic recognition molecules in development and disease. Curr Top Dev Biol. 2021:142 :319–370.33706921
Collin R , LittinkKW, KleveringBJ, van denBornLI, KoenekoopRK, ZonneveldMN, BloklandEA, StromTM, HoyngCB, den HollanderAI, et al. Identification of a 2 mb human ortholog of drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa. Am J Hum Genet. 2008:83 (5 ):594–603.18976725
Condomitti G , deWitJ. Heparan Sulfate proteoglycans as emerging players in synaptic specificity. Front Mol Neurosci. 2018:11 :14.29434536
Costa E , RezendeBA, CortesSF, LemosVS. Neuronal nitric oxide synthase in vascular physiology and diseases. Front Physiol. 2016:7 :206.27313545
Cummings R . The repertoire of glycan determinants in the human glycome. Mol BioSyst. 2009:5 (10 ):1087–1104.19756298
Cuttler K , HassanM, CarrJ, CloeteR, BardienS. Emerging evidence implicating a role for neurexins in neurodegenerative and neuropsychiatric disorders. Open Biol. 2021:11 (10 ):210091.34610269
Dai J , Liakath-AliK, GolfSR, SüdhofTC. Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner. elife. 2022:11 :e78649.36205393
de Wit J , GhoshA. Specification of synaptic connectivity by cell surface interactions. Nat Rev Neurosci. 2016:17 (1 ):22–35.26656254
Dybus A , KuligH, GrzesiakW, DomkeJ, YuYH, ChengYH. Calcium/Calmodulin-dependent serine protein kinase (CASK) gene polymorphisms in pigeons. Animals (Basel). 2023:13 (13 ):2070.37443867
Ervasti J , CampbellKP. Membrane organization of the dystrophin–glycoprotein complex. Cell. 1991:66 (6 ):1121–1131.1913804
Fallon J , HallZW. Building synapses: Agrin and dystroglycan stick together. Trends Neurosci. 1994:17 (11 ):469–473.7531888
Figiel I , BączyńskaE, WójtowiczT, MagnowskaM, BuszkaA, BijataM, WłodarczykJ. The cell adhesion protein dystroglycan affects the structural remodeling of dendritic spines. Sci Rep. 2022:12 (1 ):2506.35169214
Förstermann U , SessaWC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012:33 (7 ):829–837.21890489
Furukawa T , UenoA, OmoriY. Molecular mechanisms underlying selective synapse formation of vertebrate retinal photoreceptor cells. Cell Mol Life Sci. 2020:77 (7 ):1251–1266.31586239
Garbincius J , MicheleDE. Dystrophin-glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling. Proc Natl Acad Sci USA. 2015:112 (44 ):13663–13668.26483453
Gardner J , GhorpadeA. Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system. J Neurosci Res. 2003:74 (6 ):801–806.14648584
Gee S , MontanaroF, LindenbaumMH, CarbonettoS. Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell. 1994:77 (5 ):675–686.8205617
Gehlsen K , SriramaraoP, FurchtLT, SkubitzAP. A synthetic peptide derived from the carboxy terminus of the laminin A chain represents a binding site for the alpha 3 beta 1 integrin. J Cell Biol. 1992:117 (2 ):449–459.1560034
Goddeeris M , WuB, VenzkeD, Yoshida-MoriguchiT, SaitoF, MatsumuraK, MooreSA, CampbellKP. LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature. 2013:503 (7474 ):136–140.24132234
Gomez Toledo A , RaducuM, CrucesJ, NilssonJ, HalimA, LarsonG, RuetschiU, GrahnA. O-mannose and O–N-acetyl galactosamine glycosylation of mammalian α-dystroglycan is conserved in a region-specific manner. Glycobiology. 2012:22 (11 ):1413–1423.22781125
Gopal S , ArokiasamyS, PatakiC, WhitefordJR, CouchmanJR. Syndecan receptors: pericellular regulators in development and inflammatory disease. Open Biol. 2021:11 (2 ):200377.33561383
Gordts P , EskoJD. Heparan sulfate proteoglycans fine-tune macrophage inflammation via IFN-β. Cytokine. 2015:72 (1 ):118–119.25573804
Gros K , MatkovičU, ParatoG, MišK, LuinE, BernareggiA, SciancaleporeM, MaršT, LorenzonP, PirkmajerS. Neuronal Agrin promotes proliferation of primary human myoblasts in an age-dependent manner. Int J Mol Sci. 2022:23 (19 ):11784.36233091
Guarino S , CancianiA, FornerisF. Dissecting the extracellular complexity of neuromuscular junction organizers. Front Mol Biosci. 2020:6 :156.31998752
Guilak F , HayesAJ, MelroseJ. Perlecan in Pericellular Mechanosensory cell-matrix communication, extracellular matrix stabilisation and Mechanoregulation of load-bearing connective tissues. Int J Mol Sci. 2021:22 (5 ):2716.33800241
Harrison R , HitchenPG, PanicoM, MorrisHR, MekhaielD, PleassRJ, DellA, HewittJE, HaslamSM. Glycoproteomic characterization of recombinant mouse α-dystroglycan. Glycobiology. 2012:22 (5 ):662–675.22241827
Hayes A , MelroseJ. HS, an ancient molecular recognition and information storage glycosaminoglycan, equips HS-proteoglycans with diverse matrix and cell-interactive properties operative in tissue development and tissue function in health and disease. Int J Mol Sci. 2023:24 (2 ):1148.36674659
Hayes A , FarrugiaBL, BioseIJ, BixGJ, MelroseJ. Perlecan, a multi-functional, cell-instructive, matrix-stabilizing proteoglycan with roles in tissue development has relevance to connective tissue repair and regeneration. Front Cell Dev Biol. 2022:10 :856261.35433700
Henry M , CampbellKP. Dystroglycan inside and out. Curr Opin Cell Biol. 1999:11 (5 ):602–607.10508656
Herbst R . MuSk function during health and disease. Neurosci Lett. 2020:716 :134676.31811897
Ho A , LiuX, SüdhofTC. Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease. J Neurosci. 2008:28 (53 ):14392–14400.19118172
Hohenester E . Laminin G-like domains: dystroglycan-specific lectins. Curr Opin Struct Biol. 2019:56 :56–63.30530204
Hsueh Y . The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem. 2006:13 (16 ):1915–1927.16842202
Hubbard S , GnanasambandanK. Structure and activation of MuSK, a receptor tyrosine kinase central to neuromuscular junction formation. Biochim Biophys Acta. 2013:1834 (10 ):2166–2169.23467009
Husain N , PellikkaM, HongH, KlimentovaT, ChoeKM, ClandininTR, TepassU. The agrin/perlecan-related protein eyes shut is essential for epithelial lumen formation in the Drosophila retina. Dev Cell. 2006:11 (4 ):483–493.17011488
Ibraghimov-Beskrovnaya O , ErvastiJM, LeveilleCJ, SlaughterCA, SernettSW, CampbellKP. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature. 1992:355 (6362 ):696–702.1741056
Iroegbu J , IjomoneOK, Femi-AkinlosotuOM, IjomoneOM. ERK/MAPK signalling in the developing brain: perturbations and consequences. Neurosci Biobehav Rev. 2021:131 :792–805.34634357
Jacobson C , CôtéPD, RossiSG, RotundoRL, CarbonettoS. The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol. 2001:152 (3 ):435–450.11157973
Jahncke J , WrightKM. The many roles of dystroglycan in nervous system development and function: Dystroglycan and neural circuit development. Dev Dyn. 2023:252 (1 ):61–80.35770940
Jung D , YangB, MeyerJ, ChamberlainJS, CampbellKP. Identification and characterization of the dystrophin anchoring site on beta-dystroglycan. J Biol Chem. 1995:270 (45 ):27305–27310.7592992
Kanagawa M , OmoriY, SatoS, KobayashiK, Miyagoe-SuzukiY, TakedaS, EndoT, FurukawaT, TodaT. Post-translational maturation of dystroglycan is necessary for pikachurin binding and ribbon synaptic localization. J Biol Chem. 2010:285 (41 ):32108–32116.
Karakatsani A , MarichalN, UrbanS, KalamakisG, GhanemA, SchickA, ZhangY, ConzelmannKK, RüeggMA, BerningerB, et al. Neuronal LRP4 regulates synapse formation in the developing CNS. Development. 2017:144 (24 ):4604–4615.29061639
Kim Y , JohTH. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol Ther (Seoul). 2012:20 (2 ):133–143.24116286
Kim J , WulschnerLEG, OhWC, KoJ. Trans-synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules. BioEssays. 2022:44 :e2200134.36089658
Koike C , ObaraT, UriuY, NumataT, SanukiR, MiyataK, KoyasuT, UenoS, FunabikiK, TaniA, et al. TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proc Natl Acad Sci USA. 2010:107 (1 ):332–337.19966281
Kolb H , FernandezE, NelsonR. Webvision: the Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995.
Kosco E , JingH, ChenP, XiongWC, SamuelsIS, MeiL. DOK7 promotes NMJ regeneration after nerve injury. Mol Neurobiol. 2023:60 (3 ):1453–1464.36464749
Kramer R , VuMP, ChengYF, RamosDM, TimplR, WalehN. Laminin-binding integrin alpha 7 beta 1: functional characterization and expression in normal and malignant melanocytes. Cell Regul. 1991:2 (10 ):805–817.1839357
LaConte L , ChavanV, LiangC, WillisJ, SchönhenseEM, SchochS, MukherjeeK. CASK stabilizes neurexin and links it to liprin-α in a neuronal activity-dependent manner. Cell Mol Life Sci. 2016:73 (18 ):3599–3621.27015872
Lee A , KhaledH, ChoffletN, TakahashiH. Synaptic organizers in Alzheimer's disease: a classification based on amyloid-β sensitivity. Front Cell Neurosci. 2020:14 :281.32982693
Li L , XiongWC, MeiL. Neuromuscular junction formation, aging, and disorders. Annu Rev Physiol. 2018:80 (1 ):159–188.29195055
Lin P , HungJH, HsuCK, ChangYT, SunYT. A novel pathogenic HSPG2 mutation in Schwartz-Jampel syndrome. Front Neurol. 2021:12 :632336.33767660
Lindenmaier L , ParmentierN, GuoC, TissirF, WrightKM. Dystroglycan is a scaffold for extracellular axon guidance decisions. elife. 2019:8 :e42143.30758284
Lipper CH , KarmiO, SohnYS, Darash-YahanaM, LammertH, SongL, LiuA, MittlerR, NechushtaiR, OnuchicJN, et al. Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells. Proc Natl Acad Sci USA. 2018:115 (2 ):272–277.29259115
Lisé M , El-HusseiniA. The neuroligin and neurexin families: from structure to function at the synapse. Life Sci. 2006:63 :1833–1849.
Liu J , MisraA, Sekhar ReddyMVVV, WhiteMA, RenG, RudenkoG. Structural plasticity of Neurexin 1α: implications for its role as synaptic organizer. J Mol Biol. 2018:430 (21 ):4325–4343.30193986
Liu Y , YuM, ShangX, NguyenMHH, BalakrishnanS, SagerR, HuH. Eyes shut homolog (EYS) interacts with matriglycan of O-mannosyl glycans whose deficiency results in EYS mislocalization and degeneration of photoreceptors. Sci Rep. 2020:10 (1 ):7795.32385361
Lord M , ChuangCY, MelroseJ, DaviesMJ, IozzoRV, WhitelockJM. The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling. Matrix Biol. 2014:35 :112–122.24509440
Lu Z , HuX, LiuF, SoaresDC, LiuX, YuS, GaoM, HanS, QinY, LiC, et al. Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy. Sci Rep. 2017:7 (1 ):46098.28378834
Lukaszewicz-Zając M , MroczkoB, SłowikA. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS). J Neural Transm (Vienna). 2014:121 (11 ):1387–1397.25047909
Manya H , YamaguchiY, KanagawaM, KobayashiK, TajiriM, Akasaka-ManyaK, KawakamiH, MizunoM, WadaY, TodaT, et al. The muscular dystrophy gene TMEM5 encodes a Ribitol β1,4-Xylosyltransferase required for the functional glycosylation of Dystroglycan. J Biol Chem. 2016:291 (47 ):24618–24627.27733679
Marrone A , KucherenkoMM, RishkoVM, ShcherbataHR. New dystrophin/dystroglycan interactors control neuron behavior in drosophila eye. BMC Neurosci. 2011:12 (1 ):93.21943192
Martemyanov K , SampathAP. The transduction Cascade in retinal ON-bipolar cells: signal processing and disease. Annu Rev Vis Sci. 2017:3 (1 ):25–31.28715957
Matsuda K , MiuraE, MiyazakiT, KakegawaW, EmiK, NarumiS, FukazawaY, Ito-IshidaA, KondoT, ShigemotoR, et al. Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science. 2010:328 (5976 ):363–368.20395510
McNally EM , deSá MoreiraE, DugganDJ, BönnemannCG, LisantiMP, LidovHG, VainzofM, Passos-BuenoMR, HoffmanEP, ZatzM, et al. Caveolin-3 in muscular dystrophy. Hum Mol Genet. 1998:7 (5 ):871–877.9536092
Mead T , BhutadaS, MartinDR, ApteSS. Proteolysis: a key post-translational modification regulating proteoglycans. Am J Physiol Cell Physiol. 2022:323 (3 ):C651–C665.35785985
Mehboob M , LangM. Structure, function, and pathology of protein O-glucosyltransferases. Cell Death Dis. 2021:12 (1 ):71.33436558
Melikian N , SeddonMD, CasadeiB, ChowienczykPJ, ShahAM. Neuronal nitric oxide synthase and human vascular regulation. Trends Cardiovasc Med. 2009:19 (8 ):256–262.20447567
Melo-Filho C , SuG, LiuK, MuratovEN, TropshaA, LiuJ. Modeling interactions between Heparan Sulfate and proteins based on the Heparan Sulfate microarray analysis. Glycobiology. 2024:34 (7 ):cwae039.38836441
Melrose J . CNS/PNS proteoglycans functionalize neuronal and astrocyte niche micro-environments optimizing cellular activity by preserving membrane polarization dynamics, ionic micro-environments, ion fluxes, neuronal activation and network Neurotransductive capacity. J Neuroscienc Res. 2024: (in press).
Melrose J , HayesAJ, BixG. The CNS/PNS extracellular matrix provides instructive guidance cues to neural cells and Neuroregulatory proteins in neural development and repair. Int J Mol Sci. 2021:22 (11 ):5583.34070424
Millay DP , GoonasekeraSA, SargentMA, MailletM, AronowBJ, MolkentinJD. Calcium influx is sufficient to induce muscular dystrophy through a TRPC-dependent mechanism. Proc Natl Acad Sci USA. 2009:106 (45 ):19023–19028.19864620
Mittler R , Darash-YahanaM, SohnYS, BaiF, SongL, CabantchikIZ, JenningsPA, OnuchicJN, NechushtaiR. NEET proteins: a new Link between iron metabolism, reactive oxygen species, and cancer. Antioxid Redox Signal. 2019:30 (8 ):1083–1095.29463105
Molino D , Pila-CastellanosI, MarjaultHB, Dias AmoedoN, KoppK, RochinL, KarmiO, SohnYS, LinesL, HamaïA, et al. Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics. EMBO Rep. 2020:21 (12 ):e49019.33180995
Morgans C , BrownRL, DuvoisinRM. TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells. BioEssays. 2010:32 (7 ):609–614.20544736
Morikawa Y , HeallenT, LeachJ, XiaoY, MartinJF. Dystrophin-glycoprotein complex sequesters yap to inhibit cardiomyocyte proliferation. Nature. 2017:547 (7662 ):227–231.28581498
Mueller C , SchluesenerHJ, FauserU, ConradS, SchwabJM. Lesional expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following traumatic brain injury (TBI). Exp Neurol. 2007:208 (2 ):228–237.17942095
Nickolls A , BönnemannCG. The roles of dystroglycan in the nervous system: insights from animal models of muscular dystrophy. Dis Model Mech. 2018:11 (12 ):dmm035931.30578246
Noborn F , SterkyFH. Role of neurexin heparan sulfate in the molecular assembly of synapses - expanding the neurexin code? FEBS J. 2023:290 (2 ):252–265.34699130
Nogami K , SuzukiH, HabuchiH, IshiguroN, IwataH, KimataK. Distinctive expression patterns of heparan sulfate O-sulfotransferases and regional differences in heparan sulfate structure in chick limb buds. J Biol Chem. 2004:279 (9 ):8219–8229.14660620
Nomura A , ShigemotoR, NakamuraY, OkamotoN, MizunoN, NakanishiS. Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell. 1994:77 (3 ):361–369.8181056
O'Gallagher K , PuleddaF, 'Daly OO, RyanM, DancyL, ChowienczykPJ, ZelayaF, GoadsbyPJ, ShahAM. Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans. Cardiovasc Res. 2022:118 (5 ):1321–1329.34120160
Okuma H , HordJM, ChandelI, VenzkeD, AndersonME, WalimbeAS, JosephS, GastelZ, HaraY, SaitoF, et al. N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy. elife. 2023:12 :e82811.36723429
Omori Y , ArakiF, ChayaT, KajimuraN, IrieS, TeradaK, MuranishiY, TsujiiT, UenoS, KoyasuT, et al. Presynaptic dystroglycan-pikachurin complex regulates the proper synaptic connection between retinal photoreceptor and bipolar cells. J Neurosci. 2012:32 (18 ):6126–6137.22553019
Orlandi C , PosokhovaE, MasuhoI, RayTA, HasanN, GreggRG, MartemyanovKA. GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes. J Cell Biol. 2012:197 (6 ):711–719.22689652
Orlandi C , OmoriY, WangY, CaoY, UenoA, RouxMJ, CondomittiG, deWitJ, KanagawaM, FurukawaT, et al. Transsynaptic binding of orphan receptor GPR179 to Dystroglycan-Pikachurin complex is essential for the synaptic organization of photoreceptors. Cell Rep. 2018:25 (1 ):130–145.e5.30282023
Pan Y , TibbeD, HarmsFL, ReißnerC, BeckerK, DingmannB, MirzaaG, Kattentidt-MouravievaAA, ShoukierM, AggarwalS, et al. Missense mutations in CASK, coding for the calcium−/calmodulin-dependent serine protein kinase, interfere with neurexin binding and neurexin-induced oligomerization. J Neurochem. 2021:157 (4 ):1331–1350.33090494
Pintér P , AlpárA. The role of extracellular matrix in human neurodegenerative diseases. Int J Mol Sci. 2022:23 (19 ):11085.36232390
Praissman J , LiveDH, WangS, RamiahA, ChinoyZS, BoonsGJ, MoremenKW, WellsL. B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan. elife. 2014:3 :e03943.25279697
Praissman J , WillerT, SheikhMO, ToiA, ChitayatD, LinYY, LeeH, StalnakerSH, WangS, PrabhakarPK, et al. The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition. elife. 2016:5 :e14473.27130732
Qin L , GuoS, HanY, WangX, ZhangB. Functional mosaic organization of neuroligins in neuronal circuits. Cell Mol Life Sci. 2020:77 (16 ):3117–3127.32077971
Reily C , StewartTJ, RenfrowMB, NovakJ. Glycosylation in health and disease. Nat Rev Nephrol. 2019:15 (6 ):346–366.30858582
Reissner C , RunkelF, MisslerM. Neurexins. Genome Biol. 2013:14 (9 ):213.24083347
Rempe R , HartzAMS, BauerB. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab. 2016:36 (9 ):1481–1507.27323783
Rivera S , García-GonzálezL, KhrestchatiskyM, BarangerK. Metalloproteinases and their tissue inhibitors in Alzheimer's disease and other neurodegenerative disorders. Cell Mol Life Sci. 2019:76 (16 ):3167–3191.31197405
Roppongi R , KarimiB, SiddiquiTJ. Role of LRRTMs in synapse development and plasticity. Neurosci Res. 2017:116 :18–28.27810425
Royo M , EscolanoBA, MadrigalMP, JuradoS. AMPA receptor function in hypothalamic synapses. Front Synaptic Neurosci. 2022:14 :833449.35173598
Saito F , MooreSA, BarresiR, HenryMD, MessingA, Ross-BartaSE, CohnRD, WilliamsonRA, SlukaKA, ShermanDL, et al. Unique role of dystroglycan in peripheral nerve myelination, nodal structure, and sodium channel stabilization. Neuron. 2003:38 (5 ):747–758.12797959
Sato S , OmoriY, KatohK, KondoM, KanagawaM, MiyataK, FunabikiK, KoyasuT, KajimuraN, MiyoshiT, et al. Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation. Nat Neurosci. 2008:11 (8 ):923–931.18641643
Sciandra F , BozziM, BigottiMG. From adhesion complex to signaling hub: the dual role of dystroglycan. Front Mol Biosci. 2023:10 :1325284.38155958
Sciandra F , DesiderioC, VincenzoniF, ViscusoS, BozziM, HübnerW, Jimenez-GutierrezGE, CisnerosB, BrancaccioA. Analysis of the GFP-labelled β-dystroglycan interactome in HEK-293 transfected cells reveals novel intracellular networks. Biochem Biophys Res Commun. 2024:703 :149656.38364681
Sethi M , ZaiaJ. Extracellular matrix proteomics in schizophrenia and Alzheimer's disease. Anal Bioanal Chem. 2017:409 (2 ):379–394.27601046
Sigoillot S , BourgeoisF, LambergeonM, StrochlicL, LegayC. ColQ controls postsynaptic differentiation at the neuromuscular junction. J Neurosci. 2010:30 (1 ):13–23.20053883
Smirnov S , BarzaghiP, McKeeKK, RueggMA, YurchencoPD. Conjugation of LG domains of agrins and perlecan to polymerizing laminin-2 promotes acetylcholine receptor clustering. J Biol Chem. 2005:280 (50 ):41449–41457.16219760
Stevenson D , LavertyHG, WenwieserS, DouglasM, WilsonJB. Mapping and expression analysis of the human CASK gene. Mamm Genome. 2000:11 (10 ):934–937.11003712
Sugita S , SaitoF, TangJ, SatzJ, CampbellK, SüdhofTC. A stoichiometric complex of neurexins and dystroglycan in brain. J Cell Biol. 2001:154 (2 ):435–445.11470830
Sugita Y , ArakiF, ChayaT, KawanoK, FurukawaT, MiuraK. Role of the mouse retinal photoreceptor ribbon synapse in visual motion processing for optokinetic responses. PLoS One. 2015:10 (5 ):e0124132.25955222
Suvannaboon R , PawestriAR, JindaW, TuekprakhonA, TrinavaratA, AtchaneeyasakulLO. Genotypic and phenotypic profiles of EYS gene-related retinitis pigmentosa: a retrospective study. Sci Rep. 2022:12 (1 ):21494.36513702
Suzuki A , YoshidaM, HayashiK, MizunoY, HagiwaraY, OzawaE. Molecular organization at the glycoprotein-complex-binding site of dystrophin. Three dystrophin-associated proteins bind directly to the carboxy-terminal portion of dystrophin. Eur J Biochem. 1994:220 (2 ):283–292.8125086
Takawira D , BudingerGRS, HopkinsonSB, JonesJCR. A dystroglycan/plectin scaffold mediates mechanical pathway bifurcation in lung epithelial cells. J Biol Chem. 2011:286 (8 ):6301–6310.21149456
Talts J , AndacZ, GohringW, BrancaccioA, TimplR. Binding of the G domains of laminin α1 and α2 chains and perlecan to heparin, sulfatides, α-dystroglycan and several extracellular matrix proteins. EMBO J. 1999:18 (4 ):863–870.10022829
Tamir S , PaddockML, Darash-Yahana-BaramM, HoltSH, SohnYS, AgranatL, MichaeliD, StoflethJT, LipperCH, MorcosF, et al. Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease. Biochim Biophys Acta. 2015:1853 (6 ):1294–1315.25448035
Thompson W , ModlaS, GrindelBJ, CzymmekKJ, Kirn-SafranCB, WangL, DuncanRL, Farach-CarsonMC. Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res. 2011:26 (3 ):618–629.20814969
Traunmüller L , SchulzJ, OrtizR, FengH, FurlanisE, GomezAM, SchreinerD, BischofbergerJ, ZhangC, ScheiffeleP. A cell-type-specific alternative splicing regulator shapes synapse properties in a trans-synaptic manner. Cell Rep. 2023:42 (3 ):112173.36862556
Treutlein B , GokceO, QuakeSR, SüdhofTC. Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. Proc Natl Acad Sci USA. 2014:111 (13 ):E1291–E1299.24639501
Ullrich B , UshkaryovYA, SüdhofTC. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron. 1995:14 (3 ):497–507.7695896
Uyen Dao T , BarbeauS, MesséantJ, Della-GasperaB, BoucebaT, SemprezF, LegayC, DobbertinA. The collagen ColQ binds to LRP4 and regulates the activation of the muscle-specific kinase-LRP4 receptor complex by agrin at the neuromuscular junction. J Biol Chem. 2023:299 (8 ):104962.37356721
Vincent T , McClurgO, TroebergL. The extracellular matrix of articular cartilage controls the bioavailability of Pericellular matrix-bound growth factors to drive tissue homeostasis and repair. Int J Mol Sci. 2022:23 (11 ):6003.35682681
Wang B , LaiX, PriceC, ThompsonWR, LiW, QuabiliTR, TsengWJ, LiuXS, ZhangH, PanJ, et al. Perlecan-containing pericellular matrix regulates solute transport and mechanosensing within the osteocyte lacunar-canalicular system. J Bone Miner Res. 2014:29 (4 ):878–891.24115222
Whitelock J , MelroseJ, IozzoRV. Diverse cell signaling events modulated by perlecan. Biochemistry. 2008:47 (43 ):11174–11183.18826258
Wijeratne S , MartinezJR, GrindelBJ, FreyEW, LiJ, WangL, Farach-CarsonMC, KiangCH. Single molecule force measurements of perlecan/HSPG2: a key component of the osteocyte pericellular matrix. Matrix Biol. 2016:50 :27–38.26546708
Willer T , InamoriK, VenzkeD, HarveyC, MorgensenG, HaraY, Beltrán Valero de BernabéD, YuL, WrightKM, CampbellKP, et al. The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation. elife. 2014:3 :e03941.25279699
Winter L , WicheG. The many faces of plectin and plectinopathies: pathology and mechanisms. Acta Neuropathol. 2013:125 (1 ):77–93.22864774
Wortzel I , SegerR. The ERK Cascade: distinct functions within various subcellular organelles. Genes Cancer. 2011:2 (3 ):195–209.21779493
Yamaguchi Y . Glycobiology of the synapse: the role of glycans in the formation, maturation, and modulation of synapses. Biochim Biophys Acta. 2002:1573 (3 ):369–376.12417420
Yoshida-Moriguchi T , CampbellKP. Matriglycan: a novel polysaccharide that links dystroglycan to the basement membrane. Glycobiology. 2015:25 (7 ):702–713.25882296
Yu M , LiuY, LiJ, NataleBN, CaoS, WangD, AmackJD, HuH. Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish. Biol Open. 2016:5 (11 ):1662–1673.27737822
Yurchenco P , ChengYS, SchittnyJC. Heparin modulation of laminin polymerization. J Biol Chem. 1990:265 (7 ):3981–3991.2303489
Zhang P , LuH, PeixotoRT, PinesMK, GeY, OkuS, SiddiquiTJ, XieY, WuW, Archer-HartmannS, et al. Heparan Sulfate organizes neuronal synapses through Neurexin partnerships. Cell. 2018:174 (6 ):1450–1464.e23.30100184
Zhao Z , LiY, WangM, ZhaoS, ZhaoZ, FangJ. Mechanotransduction pathways in the regulation of cartilage chondrocyte homoeostasis. J Cell Mol Med. 2020:24 (10 ):5408–5419.32237113
Zhao X , XieWQ, XiaoWF, LiHZ, NaranmandakhS, BruyereO, ReginsterJY, LiYS. Perlecan: roles in osteoarthritis and potential treating target. Life Sci. 2023:12 :121190.
