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1.
Cell ; 162(6): 1391-403, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26359990

RESUMO

How metazoan mechanotransduction channels sense mechanical stimuli is not well understood. The NOMPC channel in the transient receptor potential (TRP) family, a mechanotransduction channel for Drosophila touch sensation and hearing, contains 29 Ankyrin repeats (ARs) that associate with microtubules. These ARs have been postulated to act as a tether that conveys force to the channel. Here, we report that these N-terminal ARs form a cytoplasmic domain essential for NOMPC mechanogating in vitro, mechanosensitivity of touch receptor neurons in vivo, and touch-induced behaviors of Drosophila larvae. Duplicating the ARs elongates the filaments that tether NOMPC to microtubules in mechanosensory neurons. Moreover, microtubule association is required for NOMPC mechanogating. Importantly, transferring the NOMPC ARs to mechanoinsensitive voltage-gated potassium channels confers mechanosensitivity to the chimeric channels. These experiments strongly support a tether mechanism of mechanogating for the NOMPC channel, providing insights into the basis of mechanosensitivity of mechanotransduction channels.


Assuntos
Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Mecanotransdução Celular , Canais de Potencial de Receptor Transitório/química , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Drosophila/citologia , Drosophila/crescimento & desenvolvimento , Canal de Potássio Kv1.2/metabolismo , Larva/citologia , Larva/metabolismo , Microtúbulos/metabolismo , Estrutura Terciária de Proteína , Tato
2.
Nature ; 493(7431): 221-5, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23222543

RESUMO

Touch sensation is essential for behaviours ranging from environmental exploration to social interaction; however, the underlying mechanisms are largely unknown. In Drosophila larvae, two types of sensory neurons, class III and class IV dendritic arborization neurons, tile the body wall. The mechanotransduction channel PIEZO in class IV neurons is essential for sensing noxious mechanical stimuli but is not involved in gentle touch. On the basis of electrophysiological-recording, calcium-imaging and behavioural studies, here we report that class III dendritic arborization neurons are touch sensitive and contribute to gentle-touch sensation. We further identify NOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) family of ion channels, as a mechanotransduction channel for gentle touch. NOMPC is highly expressed in class III neurons and is required for their mechanotransduction. Moreover, ectopic NOMPC expression confers touch sensitivity to the normally touch-insensitive class IV neurons. In addition to the critical role of NOMPC in eliciting gentle-touch-mediated behavioural responses, expression of this protein in the Drosophila S2 cell line also gives rise to mechanosensitive channels in which ion selectivity can be altered by NOMPC mutation, indicating that NOMPC is a pore-forming subunit of a mechanotransduction channel. Our study establishes NOMPC as a bona fide mechanotransduction channel that satisfies all four criteria proposed for a channel to qualify as a transducer of mechanical stimuli and mediates gentle-touch sensation. Our study also suggests that different mechanosensitive channels may be used to sense gentle touch versus noxious mechanical stimuli.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Mecanotransdução Celular/fisiologia , Subunidades Proteicas/metabolismo , Tato/fisiologia , Canais de Potencial de Receptor Transitório/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Dendritos/fisiologia , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Larva/citologia , Larva/fisiologia , Dados de Sequência Molecular , Mutação , Subunidades Proteicas/química , Subunidades Proteicas/genética , Alinhamento de Sequência , Canais de Potencial de Receptor Transitório/química , Canais de Potencial de Receptor Transitório/genética
3.
J Neurosci ; 32(40): 13679-88a, 2012 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23035080

RESUMO

Zfp423/OAZ, a multi-zinc finger protein, is proposed to participate in neuronal differentiation through interactions with the Olf/EBF (O/E) family of transcription factors and mediate extrinsic BMP signaling pathways. These activities are associated with distinct domains of the Olf/EBF-associated zinc finger (OAZ) protein. Sustained OAZ expression arrests olfactory sensory neurons (OSNs) at an immature state and alters olfactory receptor expression, but the mechanism remains elusive. We show here that constitutive expression of a C-terminal mutant OAZ (OAZΔC) in mice that selectively disrupts OAZ-O/E interaction while retaining other activities, exhibits apparently normal OSN differentiation. Additionally, interfering with potential BMP signaling pathways by inducible Follistatin expression in adult mice does not alter the neuronal lineage or differentiation status. Our results indicate that O/E-mediated processes are essential for the differentiation of OSNs and the establishment of a mature phenotype. BMP signaling pathways, if they are active in normal adult olfactory epithelium, may play a minor role in this tissue.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Proteínas de Ligação a DNA/genética , Neurogênese/genética , Neurônios Receptores Olfatórios/citologia , Mutação Puntual , Receptores Odorantes/fisiologia , Fatores de Transcrição/genética , Transcrição Gênica , Dedos de Zinco/genética , Animais , Proteínas Morfogenéticas Ósseas/fisiologia , Linhagem da Célula , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/fisiologia , Folistatina/biossíntese , Folistatina/genética , Folistatina/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Sequências Hélice-Alça-Hélice , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Olfatória/citologia , Neurônios Receptores Olfatórios/metabolismo , Fenótipo , Ligação Proteica , Mapeamento de Interação de Proteínas , Estrutura Terciária de Proteína , Receptores Odorantes/genética , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais/fisiologia , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/fisiologia , Dedos de Zinco/fisiologia
4.
Neuron ; 54(4): 547-57, 2007 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-17521568

RESUMO

The coordination of gene expression is critical for cell differentiation and the subsequent establishment of tissue function. We show here that a multiple zinc finger transcription factor, Zfp423/OAZ, is transiently expressed in newly differentiating olfactory-receptor neurons (ORNs) and has a key role in coordinating the expression of immature and mature stage-specific genes. OAZ deletion in mice impairs aspects of ORN differentiation, particularly the patterns of axonal projection to the olfactory bulb. OAZ gain-of-function experiments show that sustained OAZ expression throughout ORN maturation arrests ORN development at an immature stage and alters OR gene expression. Importantly, reintroducing OAZ expression in mature ORNs suppresses mature marker expression and reactivates immature-specific markers. Together, these experiments suggest that OAZ participates in a developmental switch regulating the transition from differentiation to maturation in ORNs.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Organogênese , Dedos de Zinco/fisiologia , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Galactosídeos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Hibridização In Situ/métodos , Marcação In Situ das Extremidades Cortadas/métodos , Indóis/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
5.
Neuron ; 67(3): 373-80, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20696376

RESUMO

The generation of coordinated body movements relies on sensory feedback from mechanosensitive proprioceptors. We have found that the proper function of NompC, a putative mechanosensitive TRP channel, is not only required for fly locomotion, but also crucial for larval crawling. Calcium imaging revealed that NompC is required for the activation of two subtypes of sensory neurons during peristaltic muscle contractions. Having isolated a full-length nompC cDNA with a protein coding sequence larger than previously predicted, we demonstrate its function by rescuing locomotion defects in nompC mutants, and further show that antibodies against the extended C terminus recognize NompC in chordotonal ciliary tips. Moreover, we show that the ankyrin repeats in NompC are required for proper localization and function of NompC in vivo and are required for association of NompC with microtubules. Taken together, our findings suggest that NompC mediates proprioception in locomotion and support its role as a mechanosensitive channel.


Assuntos
Proteínas de Drosophila/fisiologia , Canais Iônicos/fisiologia , Locomoção/fisiologia , Canais de Cátion TRPC/fisiologia , Fatores Etários , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Drosophila , Proteínas de Drosophila/genética , Canais Iônicos/genética , Larva/genética , Larva/crescimento & desenvolvimento , Larva/fisiologia , Locomoção/genética , Dados de Sequência Molecular , Valor Preditivo dos Testes , Canais de Potencial de Receptor Transitório
6.
Dev Biol ; 307(1): 43-52, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17524391

RESUMO

The dorsal midline structure is critical for patterning the developing central nervous system (CNS). We show here that Zfp423/OAZ, a multiple zinc-finger transcription factor involved in both OE/EBF and BMP-signaling pathways, is required for the proper formation of forebrain and hindbrain midline structures. During embryogenesis, OAZ is highly expressed at the dorsal neuroepithelium flanking the roof plate. OAZ-deficient mice are ataxic, attributed to the reduction of the cerebellar vermis and some regions of the hemispheres. Characterization of postnatal cerebellar development shows defects in Purkinje cell differentiation and granule cell proliferation. In the forebrain, dorsal telencephalic commissural neurons project axons, but these axons fail to cross the midline and midline glial cells are abnormally distributed. Moreover, there are malformations in midline structures including the septum, thalamus and hypothalamus, suggesting a pivotal role of OAZ in CNS midline patterning.


Assuntos
Padronização Corporal , Sistema Nervoso Central/crescimento & desenvolvimento , Cerebelo/crescimento & desenvolvimento , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição/fisiologia , Animais , Ataxia , Sistema Nervoso Central/enzimologia , Cerebelo/embriologia , Cerebelo/patologia , Proteínas de Ligação a DNA/deficiência , Embrião de Mamíferos , Camundongos , Células Neuroepiteliais/patologia , Neurônios/patologia , Prosencéfalo/patologia , Rombencéfalo/patologia , Fatores de Transcrição/deficiência , Dedos de Zinco/fisiologia
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