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1.
Cell ; 177(3): 639-653.e15, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30955885

RESUMO

Stochastic activation of clustered Protocadherin (Pcdh) α, ß, and γ genes generates a cell-surface identity code in individual neurons that functions in neural circuit assembly. Here, we show that Pcdhα gene choice involves the activation of an antisense promoter located in the first exon of each Pcdhα alternate gene. Transcription of an antisense long noncoding RNA (lncRNA) from this antisense promoter extends through the sense promoter, leading to DNA demethylation of the CTCF binding sites proximal to each promoter. Demethylation-dependent CTCF binding to both promoters facilitates cohesin-mediated DNA looping with a distal enhancer (HS5-1), locking in the transcriptional state of the chosen Pcdhα gene. Uncoupling DNA demethylation from antisense transcription by Tet3 overexpression in mouse olfactory neurons promotes CTCF binding to all Pcdhα promoters, resulting in proximity-biased DNA looping of the HS5-1 enhancer. Thus, antisense transcription-mediated promoter demethylation functions as a mechanism for distance-independent enhancer/promoter DNA looping to ensure stochastic Pcdhα promoter choice.


Assuntos
Caderinas/genética , Desmetilação do DNA , RNA Antissenso/metabolismo , RNA Longo não Codificante/genética , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/química , Fator de Ligação a CCCTC/metabolismo , Caderinas/metabolismo , Linhagem Celular , Elementos Facilitadores Genéticos , Éxons , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Família Multigênica , Neurônios/citologia , Neurônios/metabolismo , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Antissenso/genética , Transcrição Gênica
2.
Annu Rev Cell Dev Biol ; 34: 471-493, 2018 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-30296392

RESUMO

The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.


Assuntos
Caderinas/genética , Comunicação Celular/genética , Neurônios/citologia , Receptores de Superfície Celular/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Adesão Celular/genética , Humanos , Neuritos/metabolismo , Neurônios/metabolismo , Isoformas de Proteínas/genética
3.
Proc Natl Acad Sci U S A ; 110(8): E756-65, 2013 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-23388633

RESUMO

ALS results from the selective and progressive degeneration of motor neurons. Although the underlying disease mechanisms remain unknown, glial cells have been implicated in ALS disease progression. Here, we examine the effects of glial cell/motor neuron interactions on gene expression using the hSOD1(G93A) (the G93A allele of the human superoxide dismutase gene) mouse model of ALS. We detect striking cell autonomous and nonautonomous changes in gene expression in cocultured motor neurons and glia, revealing that the two cell types profoundly affect each other. In addition, we found a remarkable concordance between the cell culture data and expression profiles of whole spinal cords and acutely isolated spinal cord cells during disease progression in the G93A mouse model, providing validation of the cell culture approach. Bioinformatics analyses identified changes in the expression of specific genes and signaling pathways that may contribute to motor neuron degeneration in ALS, among which are TGF-ß signaling pathways.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Astrócitos/patologia , Neurônios Motores/patologia , Animais , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Medula Espinal/enzimologia , Medula Espinal/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Regulação para Cima
4.
Science ; 356(6336): 406-411, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28450636

RESUMO

Serotonergic neurons project their axons pervasively throughout the brain and innervate various target fields in a space-filling manner, leading to tiled arrangements of their axon terminals to allow optimal allocation of serotonin among target neurons. Here we show that conditional deletion of the mouse protocadherin α (Pcdhα) gene cluster in serotonergic neurons disrupts local axonal tiling and global assembly of serotonergic circuitries and results in depression-like behaviors. Genetic dissection and expression profiling revealed that this role is specifically mediated by Pcdhαc2, which is the only Pcdhα isoform expressed in serotonergic neurons. We conclude that, in contrast to neurite self-avoidance, which requires single-cell identity mediated by Pcdh diversity, a single cell-type identity mediated by the common C-type Pcdh isoform is required for axonal tiling and assembly of serotonergic circuitries.


Assuntos
Axônios/patologia , Caderinas/fisiologia , Depressão/genética , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismo , Animais , Caderinas/genética , Deleção de Genes , Sistema Límbico/metabolismo , Camundongos , Camundongos Mutantes , Família Multigênica , Neurônios Serotoninérgicos/metabolismo
5.
Science ; 356(6336): 411-414, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28450637

RESUMO

The vertebrate clustered protocadherin (Pcdh) cell surface proteins are encoded by three closely linked gene clusters (Pcdhα, Pcdhß, and Pcdhγ). Here, we show that all three gene clusters functionally cooperate to provide individual mouse olfactory sensory neurons (OSNs) with the cell surface diversity required for their assembly into distinct glomeruli in the olfactory bulb. Although deletion of individual Pcdh clusters had subtle phenotypic consequences, the loss of all three clusters (tricluster deletion) led to a severe axonal arborization defect and loss of self-avoidance. By contrast, when endogenous Pcdh diversity is overridden by the expression of a single-tricluster gene repertoire (α and ß and γ), OSN axons fail to converge to form glomeruli, likely owing to contact-mediated repulsion between axons expressing identical combinations of Pcdh isoforms.


Assuntos
Caderinas/genética , Rede Nervosa/crescimento & desenvolvimento , Neurogênese/genética , Neurônios Receptores Olfatórios/fisiologia , Animais , Axônios/fisiologia , Deleção de Genes , Expressão Gênica , Variação Genética , Camundongos , Camundongos Endogâmicos C57BL , Família Multigênica , Proteína Vesicular 2 de Transporte de Glutamato/genética
6.
Neuron ; 75(3): 402-9, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22884324

RESUMO

The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B-, and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here, we show that mice lacking the three C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking three A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically, mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity.


Assuntos
Caderinas/genética , Caderinas/metabolismo , Família Multigênica , Neurônios/patologia , Animais , Proteínas Relacionadas a Caderinas , Contagem de Células , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Retina/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia
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