NEWS AND VIEWS Unraveling the ribbon synapse Jakob S Satz & Kevin P Campbell A new study identifies pikachurin, a previously-unknown dystroglycan-binding protein that is critical for the apposition of photoreceptor and bipolar cell dendrites at the ribbon synapse. This work could explain some of the visual defects seen in several muscular dystrophies. Synaptogenesis requires the precise targeting syntrophin and dystrobrevin. In skeletal increase in the number of amacrine-like cells5. of axons, the apposition of presynaptic and muscle, the interactions of dystroglycan with Pikachurin transcript was undetectable in the postsynaptic termini, as well as the proper the extracellular matrix and the intracellular Otx2 conditional null retina, suggesting that the differentiation and maturation of synaptic cytoskeleton are critical for the formation of loss of pikachurin expression may contribute termini. In retinal photoreceptor ribbon synapses, a transmembrane link that confers structural to the phenotype of the Otx2 conditional null bipolar cells and horizontal cells contact rod or integrity to skeletal muscle cells. Along with mice. By monitoring pikachurin expression, the cone photoreceptors through invaginations the skeletal muscle defects, several mutations authors found that pikachurin was expressed http://www.nature.com/natureneuroscience of the photoreceptor termini. Although the that affect the expression or post- translational in prospective photoreceptors of the neuroblast mechanisms that orchestrate the development of processing of DGC components are also layer as early as embryonic day 14.5, during the the photoreceptor ribbon synapse have not been associated with brain and eye defects. DMD peak of cone genesis and the beginning of rod precisely defined, defects in photoreceptor and and BMD, the most prevalent types of muscular genesis. Furthermore, the authors observed that bipolar cell coupling have been implicated in the dystrophy, are commonly associated with learning the subcellular localization of pikachurin in the abnormal retinal physiology seen in Duchenne impairments and abnormal electroretinograms, adult retina was restricted to the synaptic cleft and Becker muscular dystrophies (DMD and although visual function is preserved. In contrast, of the ribbon synapse, near the postsynaptic BMD, respectively). In this issue of Nature brain and eye malformations (glaucoma, retinal termini of bipolar cells. Neuroscience, Sato et al.1 identify pikachurin, dysgenesis and detachment) are prominent in To characterize the effect of pikachurin a previously unknown dystroglycan-binding muscle-eye-brain disease (MEB), a severe form function on retinal development, Sato et al.1 Nature Publishing Group Group Nature Publishing –/– 8 protein, which is critical for the apposition of of congenital muscular dystrophy. generated pikachurin mice by the targeted bipolar cell dendrites to the presynaptic termini Many components of the DGC are broadly disruption of the pikachurin gene. Notably, 200 of photoreceptor ribbon synapses. This study expressed in the CNS and may have important bipolar cell dendrites in ribbon synapses © highlights the importance of the extracellular roles at the synapse. In the brain, dystroglycan of both rod and cone photoreceptors were matrix to synaptic development and may also and dystrophin are expressed at a subset completely absent in these mice. In contrast, help to explain the molecular underpinnings of GABAergic synapses2, and long-term the numbers of horizontal cell dendrites in the of the visual defects that are present in several potentiation, a proposed mechanism by which pikachurin–/– ribbon synapses were normal. muscular dystrophies. information is stored at synapses, is blunted Additionally, the tips of ON bipolar cells were Muscular dystrophies are a heterogeneous in mice with a brain-specific deletion of positive for the postsynaptic marker mGluR6, group of diseases that cause skeletal muscle dystroglycan3. The expression of dystroglycan even though they failed to form appropriate weakness and wasting. Several muscular and dystrophin coincides with the first expression contacts with the photoreceptor termini. The dystrophies are associated with mutations that of synaptic markers in the outer plexiform layer authors examined the effect of pikachurin affect the function of the dystrophin- glycoprotein of the retina4, although its synaptic function function on retinal physiology by recording complex (DGC). The core components of the is not known. The study by Sato et al.1 now electroretinogram responses under both DGC in skeletal muscle include dystrophin, suggests that dystroglycan is important in the scotopic (dark-adapted) and photopic (light- dystroglycan, the sarcoglycan/sarcospan complex, development of the ribbon synapses because of adapted) conditions, which elicit responses its ability to act as a receptor for pikachurin, an from the rods and cones, respectively. In extracellular matrix–like protein. pikachurin–/– mice, the amplitude of the b-wave, The authors are at the Howard Hughes Medical Sato et al.1 identified pikachurin by generated in part by the activity of ON bipolar Institute, Department of Molecular Physiology comparing the retinal gene-expression profiles cells, was attenuated under both scotopic and and Biophysics, and Kevin P Campbell is also of mice with a photoreceptor-specific deletion photopic conditions. Together, these results a member of the Departments of Neurology of Otx2 with that of wild-type mice. Otx2 is indicate that the ultrastructural impairment of and Internal Medicine, 4283 Carver Biomedical a homeodomain transcription factor that the pikachurin–/– ribbon synapses has a marked Research Building, 285 Newton Road, Roy J. and is important for the cell-fate determination physiological importance, affecting both Lucille A. Carver College of Medicine, University of of both rod and cone photoreceptors5. Otx2 the timing and the amplitude of the bipolar Iowa, Iowa City, Iowa 52242, USA. conditional null mice are characterized by cell response to the electrical activity of rod e-mail: [email protected] a total loss of retinal photoreceptors and an or cone photoreceptors. NATURE NEUROSCIENCE VOLUME 11 | NUMBER 8 | AUGUST 2008 857 NEWS AND VIEWS biochemically interacted with α-dystroglycan. As Ribbon synapse in the case of the interaction of α-dystroglycan with agrin or perlecan, the interaction of Bipolar cell pikachurin and α-dystroglycan was dependent on the availability of a glycoepitope recognized Bipolar cell by the IIH6 antibody. In humans and mice, the post- translational ? addition of glycans to α-dystroglycan is essential Pikachurin for α-dystroglycan ligand binding. For example, MEB, which is caused by mutations of the POMGnT1, one of the glycosyltransferases involved in the synthesis of functional Dystroglycan Photoreceptor α α-dystorglycan glycosylation, is associated with β a loss of the IIH6 glycoepitope on α-dystroglycan and a loss of dystroglycan/laminin binding in skeletal muscle10. Although the precise Dmd gene product molecular mechanism is unclear, the abnormal Photoreceptor electroretinograms observed in MEB patients11 and mouse models of the disease12 suggest that a disruption of dystroglycan-ligand interactions may also underlie the visual impairment in MEB. Mutations in the genes encoding other Pikachurin null putative glycosyltransferases (that is, Large13 Ribbon synapse and Fukutin14) in mice are also associated http://www.nature.com/natureneuroscience Bipolar cell with hypoglycosylation of dystroglycan and abnormal electroretinograms, supporting a role for dystroglycan-ligand interactions in Bipolar cell the physiology of the retina. Further analyses ? of the cellular function of pikachurin may provide important clues as to the mechanism of MEB and the rapidly expanding group of congenital muscular dystrophies that are associated with defects in the post-translational α Dystroglycan processing of dystroglycan. Nature Publishing Group Group Nature Publishing 1 8 Sato et al. suggest that pikachurin may β Photoreceptor control the apposition of photoreceptor and 200 bipolar cell dendrites, either as an attractant or as © a structural component, during the development Dmd gene product of the photoreceptor ribbon synapse (Fig. 1). In the first scenario, pikachurin might attract Photoreceptor the bipolar cell dendrites through an unknown factor on the bipolar cell postsynaptic termini. Kim Caesar Kim Alternatively, binding of pikachurin may cause a structural change in the photoreceptor Figure 1 Pikachurin is necessary for the apposition of photoreceptor and bipolar cell termini. presynaptic terminus that is necessary for the (a) Bipolar cell processes contact photoreceptors through invaginations of the photoreceptor termini. proper apposition of the bipolar cell dendrites. Pikachurin binds to α-dystroglycan in the synaptic cleft. Sato et al.1 propose that pikachurin mediates Such a structural change may involve a the apposition of the presynaptic and postsynaptic termini by inducing a structural change in the rearrangement of the intracellular cytoskeleton photoreceptor terminus or by attracting the postsynaptic terminus through an unknown factor. (b) In pikachurin−/− mice, bipolar cell processes fail to extend into the photoreceptor ribbon synapses. or the extracellular matrix. In support of The alteration of synapse ultrastructure impairs synaptic physiology. ?, unknown factor. this hypothesis, the extracellular matrix has previously