The Nogo Receptor Family Restricts Synapse Number in the Developing Hippocampus

Wills, Zachary P.; Mandel‐Brehm, Caleigh; Mardinly, Alan R.; McCord, Alejandra E.; Giger, Roman J.; Greenberg, Michael E.

doi:10.1016/j.neuron.2011.11.029

Cited by 125 publications

(184 citation statements)

References 33 publications

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“…Our morphological analysis showed that Nogo-A has a negative influence on the size of the PC bodies as well as the thickness, length, and complexity of PC dendrites. These results are well in line with previous studies in adult animals showing that Nogo-A is a negative regulator of the neuronal growth program (3,29), as well as with the recent findings showing negative regulation of dendritic length and complexity by Nogo-A and NgR1 in hippocampal neurons (7,30). PC dendrites are tightly packed and intermingled in the developing ML, and they were suggested to express NgR1 (31,32).…”

Section: Discussionsupporting

confidence: 92%

“…Nevertheless, by binding to NgR1 or another yet unidentified receptor, Nogo-A activates the small GTPase RhoA (33), which has been shown to slow dendritic branch formation, yielding smaller and fewer branched dendritic arbors in various types of neurons (34). Notably, activation of RhoA has been recently identified as a mechanism by which NgR1 restricts dendritic growth and synapse formation in hippocampal neurons (30). Additionally, several studies have demonstrated that synaptic activity affects the dendritic arbor development (35,36), thus opening the possibility that by negatively regulating synaptic transmission at PF-PC synapses, Nogo-A in turn negatively regulates dendritic growth.…”

Section: Discussionmentioning

confidence: 99%

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Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum

Petrinovic

Hourez

Aloy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal signal integration as well as synaptic transmission and plasticity highly depend on the morphology of dendrites and their spines. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. Nogo-A is also expressed by certain neurons, in particular during development, but its physiological function in this cell type is less well understood. We addressed this question in the cerebellum, where Nogo-A is transitorily highly expressed in the Purkinje cells (PCs) during early postnatal development. We used general genetic ablation (KO) as well as selective overexpression of Nogo-A in PCs to analyze its effect on dendritogenesis and on the formation of their main input synapses from parallel (PFs) and climbing fibers (CFs). PC dendritic trees were larger and more complex in Nogo-A KO mice and smaller than in wild-type in Nogo-A overexpressing PCs. Nogo-A KO resulted in premature soma-to-dendrite translocation of CFs and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF-PC synapses was negatively correlated with the Nogo-A expression level. Electrophysiological studies revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF-PC synapse. Thus, Nogo-A appears as a negative regulator of PC input synapses, which orchestrates cerebellar connectivity through regulation of synapse morphology and the size of the PC dendritic tree.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum

Petrinovic

Hourez

Aloy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Several proteins have been shown previously to decrease the density of mammalian synapses, including Ephexin 5 (RhoA guanine nucleotide exchange factor) and Nogo receptors (41,42). In addition, regulator of synaptogenesis-1 (RSY-1) has been shown to regulate SYD-2/liprin-α-mediated presynaptic assembly negatively in Caenorhabditis elegans (43).…”

Section: Discussionmentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

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“…16,17 In the adult CNS, the expression of neuronal Nogo-A remains elevated mainly in plastic regions such as in the hippocampus, olfactory bulb or neocortex, and in the dorsal root ganglia. 12 Nogo-A and NgR1 were shown to regulate synaptic plasticity, for example, long-term potentiation in the hippocampus and in the sensory-motor cortex, [18][19][20][21][22] whereas the effects of neuronal Nogo-A after injury are not yet well understood. During development, neuronal Nogo-A influences neuronal migration, 23,24 survival, 25,26 cell spreading and neurite growth.…”

mentioning

confidence: 99%

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ xRtn4 flox/flox ) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4 flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

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The Nogo Receptor Family Restricts Synapse Number in the Developing Hippocampus

Cited by 125 publications

References 33 publications

Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum

Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

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