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1.
Development ; 147(4)2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31988188

RESUMO

Dendrites develop elaborate morphologies in concert with surrounding glia, but the molecules that coordinate dendrite and glial morphogenesis are mostly unknown. C. elegans offers a powerful model for identifying such factors. Previous work in this system examined dendrites and glia that develop within epithelia, similar to mammalian sense organs. Here, we focus on the neurons BAG and URX, which are not part of an epithelium but instead form membranous attachments to a single glial cell at the nose, reminiscent of dendrite-glia contacts in the mammalian brain. We show that these dendrites develop by retrograde extension, in which the nascent dendrite endings anchor to the presumptive nose and then extend by stretching during embryo elongation. Using forward genetic screens, we find that dendrite development requires the adhesion protein SAX-7/L1CAM and the cytoplasmic protein GRDN-1/CCDC88C to anchor dendrite endings at the nose. SAX-7 acts in neurons and glia, while GRDN-1 acts in glia to non-autonomously promote dendrite extension. Thus, this work shows how glial factors can help to shape dendrites, and identifies a novel molecular mechanism for dendrite growth by retrograde extension.


Assuntos
Encéfalo/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Proteínas dos Microfilamentos/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Neuroglia/fisiologia , Alelos , Animais , Caenorhabditis elegans/fisiologia , Membrana Celular/fisiologia , Citoplasma/fisiologia , Dendritos/fisiologia , Epitélio/fisiologia , Neurogênese , Isoformas de Proteínas , Células Receptoras Sensoriais/fisiologia
2.
PLoS Biol ; 17(12): e3000522, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31805038

RESUMO

In epithelia, tricellular vertices are emerging as important sites for the regulation of epithelial integrity and function. Compared to bicellular contacts, however, much less is known. In particular, resident proteins at tricellular vertices were identified only at occluding junctions, with none known at adherens junctions (AJs). In a previous study, we discovered that in Drosophila embryos, the adhesion molecule Sidekick (Sdk), well-known in invertebrates and vertebrates for its role in the visual system, localises at tricellular vertices at the level of AJs. Here, we survey a wide range of Drosophila epithelia and establish that Sdk is a resident protein at tricellular AJs (tAJs), the first of its kind. Clonal analysis showed that two cells, rather than three cells, contributing Sdk are sufficient for tAJ localisation. Super-resolution imaging using structured illumination reveals that Sdk proteins form string-like structures at vertices. Postulating that Sdk may have a role in epithelia where AJs are actively remodelled, we analysed the phenotype of sdk null mutant embryos during Drosophila axis extension using quantitative methods. We find that apical cell shapes are abnormal in sdk mutants, suggesting a defect in tissue remodelling during convergence and extension. Moreover, adhesion at apical vertices is compromised in rearranging cells, with apical tears in the cortex forming and persisting throughout axis extension, especially at the centres of rosettes. Finally, we show that polarised cell intercalation is decreased in sdk mutants. Mathematical modelling of the cell behaviours supports the notion that the T1 transitions of polarised cell intercalation are delayed in sdk mutants, in particular in rosettes. We propose that this delay, in combination with a change in the mechanical properties of the converging and extending tissue, causes the abnormal apical cell shapes in sdk mutant embryos.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Proteínas do Olho/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Junções Íntimas/fisiologia , Junções Aderentes/metabolismo , Animais , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Polaridade Celular/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/metabolismo , Epitélio/metabolismo , Proteínas do Olho/fisiologia , Proteínas de Membrana/metabolismo , Moléculas de Adesão de Célula Nervosa/fisiologia
3.
Neuron ; 99(2): 329-344.e7, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29983322

RESUMO

Pyramidal neurons express rich repertoires of leucine-rich repeat (LRR)-containing adhesion molecules with similar synaptogenic activity in culture. The in vivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.


Assuntos
Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Sinapses/fisiologia , Animais , Células Cultivadas , Técnicas de Cocultura , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Células HEK293 , Humanos , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/ultraestrutura , Proteínas de Membrana/análise , Proteínas de Membrana/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/análise , Moléculas de Adesão de Célula Nervosa/ultraestrutura , Ratos , Ratos Wistar , Sinapses/química , Sinapses/ultraestrutura , Transmissão Sináptica/fisiologia
4.
Mol Cells ; 41(5): 373-380, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29665671

RESUMO

Synapses and neural circuits form with exquisite specificity during brain development to allow the precise and appropriate flow of neural information. Although this property of synapses and neural circuits has been extensively investigated for more than a century, molecular mechanisms underlying this property are only recently being unveiled. Recent studies highlight several classes of cell-surface proteins as organizing hubs in building structural and functional architectures of specific synapses and neural circuits. In the present mini-review, we discuss recent findings on various synapse organizers that confer the distinct properties of specific synapse types and neural circuit architectures in mammalian brains, with a particular focus on the hippocampus and cerebellum.


Assuntos
Cerebelo/fisiologia , Hipocampo/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Adesão Celular , Cerebelo/citologia , Córtex Entorrinal/citologia , Córtex Entorrinal/fisiologia , Hipocampo/citologia , Humanos , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Células de Purkinje/fisiologia
5.
Development ; 145(3)2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29361567

RESUMO

The assembly of functional neuronal circuits requires growth cones to extend in defined directions and recognize the correct synaptic partners. Homophilic adhesion between vertebrate Sidekick proteins promotes synapse formation between retinal neurons involved in visual motion detection. We show here that Drosophila Sidekick accumulates in specific synaptic layers of the developing motion detection circuit and is necessary for normal optomotor behavior. Sidekick is required in photoreceptors, but not in their target lamina neurons, to promote the alignment of lamina neurons into columns and subsequent sorting of photoreceptor axons into synaptic modules based on their precise spatial orientation. Sidekick is also localized to the dendrites of the direction-selective T4 and T5 cells, and is expressed in some of their presynaptic partners. In contrast to its vertebrate homologs, Sidekick is not essential for T4 and T5 to direct their dendrites to the appropriate layers or to receive synaptic contacts. These results illustrate a conserved requirement for Sidekick proteins in establishing visual motion detection circuits that is achieved through distinct cellular mechanisms in Drosophila and vertebrates.


Assuntos
Proteínas de Drosophila/fisiologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/fisiologia , Proteínas do Olho/fisiologia , Percepção de Movimento/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Células Fotorreceptoras de Invertebrados/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas do Olho/genética , Feminino , Genes de Insetos , Masculino , Mutação , Moléculas de Adesão de Célula Nervosa/genética , Células Fotorreceptoras de Invertebrados/citologia , Sinapses/metabolismo , Vias Visuais/citologia , Vias Visuais/crescimento & desenvolvimento , Vias Visuais/fisiologia
6.
Biochem Biophys Res Commun ; 494(1-2): 120-125, 2017 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-29050943

RESUMO

Pathogen avoidance behaviors are found throughout the animal kingdom and are important for animal's survival in nature. As a free-living nematode, C. elegans is exposed to a variety of microorganisms, including toxic or pathogenic bacteria, in soil. C. elegans can develop efficient avoidance responses to pathogenic bacteria to minimize the infection risk. However, the role of microRNAs (miRNAs) in pathogen avoidance in C. elegans remains unclear. In this report, we showed that the miRNA mir-67 was involved in a behavioral avoidance response to P. aeruginosa PA14. Exposure to P. aeruginosa PA14 induced the expression of mir-67 in worms. mir-67(n4899) mutants exhibited a reduced ability to avoid P. aeruginosa PA14. By combining quantitative proteomic analysis with miRNA target prediction algorithms, we identified SAX-7/L1CAM, which is transmembrane cell adhesion receptor molecule, as the target of mir-67. Silencing of sax-7 by RNAi on mir-67 mutants rescued avoidance behavioral. Our data demonstrate that the mir-67-SAX-7 pathway modulate the behavioral avoidance response to pathogens, thus providing a new perspective in the role of miRNAs in host-microbe interactions.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , MicroRNAs/genética , RNA de Helmintos/genética , Animais , Aprendizagem da Esquiva/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/fisiologia , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais
7.
J Neurosci ; 37(41): 9828-9843, 2017 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-28871037

RESUMO

The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.


Assuntos
Moléculas de Adesão de Célula Nervosa/fisiologia , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia , Sinapses/fisiologia , Animais , Animais Recém-Nascidos , Técnicas de Cocultura , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas de Silenciamento de Genes , Células HEK293 , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moléculas de Adesão de Célula Nervosa/genética , Técnicas de Patch-Clamp , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
8.
Front Neural Circuits ; 11: 19, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28386219

RESUMO

The neural cell adhesion molecule (NCAM), has been shown to be an obligate regulator of synaptic stability and pruning during critical periods of cortical maturation. However, the functional consequences of NCAM deletion on the organization of inhibitory circuits in cortex are not known. In vesicular gamma-amino butyric acid (GABA) transporter (VGAT)-channelrhodopsin2 (ChR2)-enhanced yellow fluorescent protein (EYFP) transgenic mice, NCAM is expressed postnatally at perisomatic synaptic puncta of EYFP-labeled parvalbumin, somatostatin and calretinin-positive interneurons, and in the neuropil in the anterior cingulate cortex (ACC). To investigate how NCAM deletion affects the spatial organization of inhibitory inputs to pyramidal cells, we used laser scanning photostimulation in brain slices of VGAT-ChR2-EYFP transgenic mice crossed to either NCAM-null or wild type (WT) mice. Laser scanning photostimulation revealed that NCAM deletion increased the strength of close-in inhibitory connections to layer 2/3 pyramidal cells of the ACC. In addition, in NCAM-null mice, the intrinsic excitability of pyramidal cells increased, whereas the intrinsic excitability of GABAergic interneurons did not change. The increase in inhibitory tone onto pyramidal cells, and the increased pyramidal cell excitability in NCAM-null mice will alter the delicate coordination of excitation and inhibition (E/I coordination) in the ACC, and may be a factor contributing to circuit dysfunction in diseases such as schizophrenia and bipolar disorder, in which NCAM has been implicated.


Assuntos
Fenômenos Eletrofisiológicos/fisiologia , Giro do Cíngulo/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Células Piramidais/fisiologia , Animais , Giro do Cíngulo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Microscopia Confocal , Inibição Neural/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/citologia
9.
Nat Neurosci ; 20(5): 690-699, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346453

RESUMO

Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.


Assuntos
Código das Histonas/fisiologia , Histonas/fisiologia , Memória/fisiologia , Animais , Técnicas de Cocultura , Condicionamento Psicológico/fisiologia , Epigênese Genética , Feminino , Fatores de Transcrição GATA , Hipocampo/fisiologia , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Aprendizagem/fisiologia , Masculino , Metiltransferases/metabolismo , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Moléculas de Adesão de Célula Nervosa/fisiologia , Neurônios/metabolismo , Cultura Primária de Células , Isoformas de Proteínas/metabolismo , Proteínas Repressoras/metabolismo
10.
Neurosci Res ; 116: 29-38, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27884699

RESUMO

Cell adhesion molecules (CAMs) play essential roles in the central nervous system, where some families are involved in synaptic development and function. These synaptic adhesion molecules (SAMs) are involved in the regulation of synaptic plasticity, and the formation of neuronal networks. Recent findings from studies examining the consequences of sleep loss suggest that these molecules are candidates to act in sleep regulation. This review highlights the experimental data that lead to the identification of SAMs as potential sleep regulators, and discusses results supporting that specific SAMs are involved in different aspects of sleep regulation. Further, some potential mechanisms by which SAMs may act to regulate sleep are outlined, and the proposition that these molecules may serve as molecular machinery in the two sleep regulatory processes, the circadian and homeostatic components, is presented. Together, the data argue that SAMs regulate the neuronal plasticity that underlies sleep and wakefulness.


Assuntos
Moléculas de Adesão de Célula Nervosa/fisiologia , Sono/fisiologia , Animais , Comunicação Celular , Ritmo Circadiano , Humanos , Moléculas de Adesão de Célula Nervosa/genética , Neuroglia/fisiologia , Plasticidade Neuronal , Neurônios/fisiologia , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/fisiopatologia , Sinapses/metabolismo , Vigília/fisiologia
11.
Development ; 143(22): 4224-4235, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27707798

RESUMO

The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain- and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1-induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.


Assuntos
Dendritos/fisiologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Hipocampo/crescimento & desenvolvimento , Moléculas de Adesão de Célula Nervosa/fisiologia , Neurogênese/genética , Plasticidade Neuronal/genética , Animais , Diferenciação Celular/genética , Células Cultivadas , Embrião de Mamíferos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Complexos Multiproteicos/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Rede Nervosa/metabolismo , Neurônios/fisiologia , Ligação Proteica , Ratos , Ratos Wistar
12.
Dev Biol ; 419(2): 285-297, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27618756

RESUMO

Collective cell migration is the coordinated movement of cells, which organize tissues during morphogenesis, repair and some cancers. The motile cell membrane of the advancing front in collective cell migration is termed the Leading Edge. The embryonic development of the vertebrate and Drosophila hearts are both characterized by the coordinated medial migration of a bilateral cluster of mesodermal cells. In Drosophila, the cardioblasts form cohesive bilateral rows that migrate collectively as a unit towards the dorsal midline to form the dorsal vessel. We have characterized the collective cell migration of cardioblasts as an in vivo quantitative model to study the behaviour of the Leading Edge. We investigated whether guidance signalling through Slit and Netrin pathways plays a role in cell migration during heart development. Through time-lapse imaging and quantitative assessment of migratory behaviour of the cardioblasts in loss-of-function mutants, we demonstrate that both Slit and Netrin mediated signals are autonomously and concomitantly required to maximize migration velocity, filopodial and lamellipodial activities. Additionally, we show that another Slit and Netrin receptor, Dscam1, the role of which during heart development was previously unknown, is required for both normal migration of cardioblasts and luminal expansion. Leading edge behaviour analysis revealed a dosage dependent genetic interaction between Slit and Netrin receptors suggesting that downstream signalling through these receptors converge on a common output that increases leading edge activity of the cardioblasts. Finally, we found that guidance signalling maintains the balance between epithelial and mesenchymal characteristics of the migrating cardioblasts.


Assuntos
Movimento Celular/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/crescimento & desenvolvimento , Coração/embriologia , Miócitos Cardíacos/citologia , Pseudópodes/fisiologia , Células-Tronco/citologia , Animais , Orientação de Axônios , Moléculas de Adesão Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Transição Epitelial-Mesenquimal , Proteínas Luminescentes/análise , Morfogênese , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores de Netrina , Netrina-1 , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/fisiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Transdução de Sinais , Imagem com Lapso de Tempo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia
13.
Neuron ; 91(5): 1052-1068, 2016 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-27608760

RESUMO

Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Córtex Cerebral/fisiologia , Cognição/fisiologia , Proteínas Ligadas por GPI/fisiologia , Haploinsuficiência/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Proteína 4 Homóloga a Disks-Large , Potenciais Pós-Sinápticos Excitadores/fisiologia , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/genética , Guanilato Quinases/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/fisiologia , Moléculas de Adesão de Célula Nervosa/biossíntese , Moléculas de Adesão de Célula Nervosa/genética , Receptores de AMPA/metabolismo , Receptores de AMPA/fisiologia , Sinapses/metabolismo
14.
Science ; 352(6288): 982-6, 2016 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-27174676

RESUMO

Alternative RNA splicing represents a central mechanism for expanding the coding power of genomes. Individual RNA-binding proteins can control alternative splicing choices in hundreds of RNA transcripts, thereby tuning amounts and functions of large numbers of cellular proteins. We found that the RNA-binding protein SLM2 is essential for functional specification of glutamatergic synapses in the mouse hippocampus. Genome-wide mapping revealed a markedly selective SLM2-dependent splicing program primarily consisting of only a few target messenger RNAs that encode synaptic proteins. Genetic correction of a single SLM2-dependent target exon in the synaptic recognition molecule neurexin-1 was sufficient to rescue synaptic plasticity and behavioral defects in Slm2 knockout mice. These findings uncover a highly selective alternative splicing program that specifies synaptic properties in the central nervous system.


Assuntos
Processamento Alternativo , Ácido Glutâmico/fisiologia , Neurônios/fisiologia , Proteínas de Ligação a RNA/fisiologia , Sinapses/fisiologia , Animais , Comportamento Animal , Éxons , Estudo de Associação Genômica Ampla , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Deleção de Sequência , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
15.
Neuron ; 89(3): 423-5, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26844824

RESUMO

The modular reiterative pattern of the fly visual system makes it an ideal model to study axon guidance and synaptogenesis. In this issue of Neuron, Tadros et al. (2016) show that Dscam2/4 promote the anchoring of dendrites to their targets.


Assuntos
Dendritos/fisiologia , Proteínas de Drosophila/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Animais
16.
Neuron ; 89(3): 480-93, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26844831

RESUMO

Cell recognition molecules are key regulators of neural circuit assembly. The Dscam family of recognition molecules in Drosophila has been shown to regulate interactions between neurons through homophilic repulsion. This is exemplified by Dscam1 and Dscam2, which together repel dendrites of lamina neurons, L1 and L2, in the visual system. By contrast, here we show that Dscam2 directs dendritic targeting of another lamina neuron, L4, through homophilic adhesion. Through live imaging and genetic mosaics to dissect interactions between specific cells, we show that Dscam2 is required in L4 and its target cells for correct dendritic targeting. In a genetic screen, we identified Dscam4 as another regulator of L4 targeting which acts with Dscam2 in the same pathway to regulate this process. This ensures tiling of the lamina neuropil through heterotypic interactions. Thus, different combinations of Dscam proteins act through distinct mechanisms in closely related neurons to pattern neural circuits.


Assuntos
Dendritos/fisiologia , Proteínas de Drosophila/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Alelos , Animais , Adesão Celular/genética , Adesão Celular/fisiologia , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Drosophila melanogaster , Mosaicismo , Moléculas de Adesão de Célula Nervosa/biossíntese , Moléculas de Adesão de Célula Nervosa/genética
17.
Brain Struct Funct ; 221(3): 1591-605, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25596866

RESUMO

The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and post-natal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired long-term but not short-term memory in both, spatial and non-spatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.


Assuntos
Ambiente Controlado , Hipocampo/enzimologia , Memória/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Sialiltransferases/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurogênese , Plasticidade Neuronal , Sialiltransferases/genética , Memória Espacial/fisiologia
18.
Cell Rep ; 12(10): 1618-30, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26321637

RESUMO

Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3(-/-)) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3(-/-) mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior.


Assuntos
Moléculas de Adesão de Célula Nervosa/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/fisiologia , Processamento Alternativo , Animais , Diferenciação Celular , Potenciais Pós-Sinápticos Excitadores , Éxons , Hipocampo/citologia , Hipocampo/metabolismo , Aprendizagem , Locomoção , Camundongos Knockout , Plasticidade Neuronal , Isoformas de Proteínas/fisiologia , Desempenho Psicomotor , Sítios de Splice de RNA , Transmissão Sináptica
19.
Neurobiol Aging ; 35(4): 746-56, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24211009

RESUMO

Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in ß-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Moléculas de Adesão de Célula Nervosa/fisiologia , Sinapses/genética , Acetilcolinesterase/fisiologia , Processamento Alternativo/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Moléculas de Adesão Celular Neuronais , Comunicação Celular/genética , Comunicação Celular/fisiologia , Progressão da Doença , Humanos , Aprendizagem , Memória , Proteínas do Tecido Nervoso , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Sinapses/patologia , Sinapses/fisiologia
20.
Stress ; 16(6): 647-54, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24010949

RESUMO

The neural cell adhesion molecule (NCAM) is a key regulator of brain plasticity. Substantial evidence indicates that NCAM is down-regulated by exposure to sustained stress and chronic stress seems to lead to increased aggression. In addition, constitutional NCAM deletion in mice has been shown to lead to increased intermale aggression and altered emotionality Forebrain-specific postnatal NCAM knockout was previously shown to impair cognitive function, particularly when animals were exposed to subchronic stress, but the effects on emotional and social behavior remain unclear. In this study, we investigated the potential interplay of a forebrain-specific postnatal NCAM deletion and exposure to different lengths of repeated stress (i.e. subchronic: 14 days; chronic: 29 days) on aggressive and emotional behavior. Our results show that postnatal deletion of NCAM in the forebrain leads to increased aggression and altered emotionality depending on the duration of stress, whereas conditional NCAM knockout has no basal impact on these behaviors. These findings support the involvement of NCAM in the regulation of emotional and aggressive behaviors, suggesting that diminished NCAM expression might be a critical vulnerability factor for the development of these behavioral alterations under repeated exposure to stress.


Assuntos
Agressão/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Prosencéfalo/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/metabolismo , Comportamento Exploratório/fisiologia , Masculino , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/deficiência
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