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1.
Development ; 140(7): 1560-72, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23482491

RESUMO

The structure and function of primary cilia are critically dependent on intracellular trafficking pathways that transport ciliary membrane and protein components. The mechanisms by which these trafficking pathways are regulated are not fully characterized. Here we identify the transmembrane protein OSTA-1 as a new regulator of the trafficking pathways that shape the morphology and protein composition of sensory cilia in C. elegans. osta-1 encodes an organic solute transporter alpha-like protein, mammalian homologs of which have been implicated in membrane trafficking and solute transport, although a role in regulating cilia structure has not previously been demonstrated. We show that mutations in osta-1 result in altered ciliary membrane volume, branch length and complexity, as well as defects in localization of a subset of ciliary transmembrane proteins in different sensory cilia types. OSTA-1 is associated with transport vesicles, localizes to a ciliary compartment shown to house trafficking proteins, and regulates both retrograde and anterograde flux of the endosome-associated RAB-5 small GTPase. Genetic epistasis experiments with sensory signaling, exocytic and endocytic proteins further implicate OSTA-1 as a crucial regulator of ciliary architecture via regulation of cilia-destined trafficking. Our findings suggest that regulation of transport pathways in a cell type-specific manner contributes to diversity in sensory cilia structure and might allow dynamic remodeling of ciliary architecture via multiple inputs.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans , Cílios/genética , Membranas Intracelulares/metabolismo , Proteínas de Membrana Transportadoras/fisiologia , Animais , Animais Geneticamente Modificados , Transporte Biológico/genética , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cílios/fisiologia , Cílios/ultraestrutura , Embrião não Mamífero , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Redes e Vias Metabólicas/genética , Modelos Biológicos , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/ultraestrutura , Tamanho do Órgão/genética
2.
Front Cell Dev Biol ; 8: 777, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850869

RESUMO

Primary cilia are specialized cellular structures that project from the surface of most cell types in metazoans and mediate transduction of major signaling pathways. The ciliary membrane is contiguous with the plasma membrane, yet it exhibits distinct protein and lipid composition, which is essential for ciliary function. Diffusion barriers at the base of a cilium are responsible for establishing unique molecular composition of this organelle. Although considerable progress has been made in identifying mechanisms of ciliary protein trafficking in and out of cilia, it remains largely unknown how the distinct lipid identity of the ciliary membrane is achieved. In this mini review, I summarize recent developments in characterizing lipid composition and organization of the ciliary membrane and discuss the emerging roles of lipids in modulating activity of ciliary signaling components including ion channels and G protein-coupled receptors.

3.
Cilia ; 6: 9, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28770089

RESUMO

The free-living nematode, Caenorhabditis elegans, is a widely used genetic model organism for investigations into centriole and cilia biology. Only sensory neurons are ciliated in C. elegans; morphologically diverse cilia in these neurons are nucleated by basal bodies located at the dendritic endings. C. elegans centrioles comprise a central tube with a symmetric array of nine singlet microtubules. These singlet microtubules remodel in a subset of sensory neurons to form the doublet microtubules of the basal bodies. Following initiation of ciliogenesis, the central tube, but not the outer centriole wall, of the basal body degenerates. Recent ultrastructural characterization of basal body architecture and remodeling have laid the foundation for future studies into mechanisms underlying different aspects of basal body genesis, remodeling, and intracellular positioning.

4.
Elife ; 62017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28411364

RESUMO

The primary cilium is nucleated by the mother centriole-derived basal body (BB) via as yet poorly characterized mechanisms. BBs have been reported to degenerate following ciliogenesis in the C. elegans embryo, although neither BB architecture nor early ciliogenesis steps have been described in this organism. In a previous study (Doroquez et al., 2014), we described the three-dimensional morphologies of sensory neuron cilia in adult C. elegans hermaphrodites at high resolution. Here, we use serial section electron microscopy and tomography of staged C. elegans embryos to demonstrate that BBs remodel to support ciliogenesis in a subset of sensory neurons. We show that centriolar singlet microtubules are converted into BB doublets which subsequently grow asynchronously to template the ciliary axoneme, visualize degeneration of the centriole core, and define the developmental stage at which the transition zone is established. Our work provides a framework for future investigations into the mechanisms underlying BB remodeling.


Assuntos
Caenorhabditis elegans/citologia , Caenorhabditis elegans/embriologia , Centríolos/metabolismo , Cílios/genética , Cílios/metabolismo , Biogênese de Organelas , Animais , Corpos Basais/metabolismo , Corpos Basais/ultraestrutura , Centríolos/ultraestrutura , Cílios/ultraestrutura , Tomografia com Microscopia Eletrônica , Microscopia Eletrônica , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/fisiologia
5.
J Cell Biol ; 214(4): 459-74, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27502486

RESUMO

FoxO proteins are evolutionarily conserved regulators of neuronal structure and function, yet the neuron-specific pathways within which they act are poorly understood. To elucidate neuronal FoxO function in Drosophila melanogaster, we first screened for FoxO's upstream regulators and downstream effectors. On the upstream side, we present genetic and molecular pathway analyses indicating that the Toll-6 receptor, the Toll/interleukin-1 receptor domain adaptor dSARM, and FoxO function in a linear pathway. On the downstream side, we find that Toll-6-FoxO signaling represses the mitotic kinesin Pavarotti/MKLP1 (Pav-KLP), which itself attenuates microtubule (MT) dynamics. We next probed in vivo functions for this novel pathway and found that it is essential for axon transport and structural plasticity in motoneurons. We demonstrate that elevated expression of Pav-KLP underlies transport and plasticity phenotypes in pathway mutants, indicating that Toll-6-FoxO signaling promotes MT dynamics by limiting Pav-KLP expression. In addition to uncovering a novel molecular pathway, our work reveals an unexpected function for dynamic MTs in enabling rapid activity-dependent structural plasticity.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Neurônios Motores/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Animais , Proteínas do Domínio Armadillo/metabolismo , Axônios/metabolismo , Núcleo Celular/metabolismo , Sistema Nervoso Central/metabolismo , Proteínas do Citoesqueleto/metabolismo , Modelos Biológicos , Mutação/genética , Junção Neuromuscular/metabolismo , Plasticidade Neuronal , Transporte Proteico , Sinapses/metabolismo
6.
Dev Cell ; 38(5): 493-506, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27623382

RESUMO

Primary cilia are ubiquitous sensory organelles that mediate diverse signaling pathways. Cilia position on the cell surface is determined by the location of the basal body (BB) that templates the cilium. The mechanisms that regulate BB positioning in the context of ciliogenesis are largely unknown. Here we show that the conserved signaling and scaffolding protein Girdin localizes to the proximal regions of centrioles and regulates BB positioning and ciliogenesis in Caenorhabditis elegans sensory neurons and human RPE-1 cells. Girdin depletion alters localization of the intercentriolar linker and ciliary rootlet component rootletin, and rootletin knockdown in RPE-1 cells mimics Girdin-dependent phenotypes. C. elegans Girdin also regulates localization of the apical junction component AJM-1, suggesting that in nematodes Girdin may position BBs via rootletin- and AJM-1-dependent anchoring to the cytoskeleton and plasma membrane, respectively. Together, our results describe a conserved role for Girdin in BB positioning and ciliogenesis.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Cílios/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas dos Microfilamentos/genética , Morfogênese/genética , Proteínas de Transporte Vesicular/genética , Animais , Corpos Basais/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/biossíntese , Centríolos/genética , Cílios/genética , Citoesqueleto/genética , Humanos , Proteínas dos Microfilamentos/biossíntese , Microtúbulos/genética , Organelas/genética , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/genética , Proteínas de Transporte Vesicular/biossíntese
7.
Mol Cells ; 36(4): 288-303, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24048681

RESUMO

Primary non-motile cilia and dendritic spines are cellular compartments that are specialized to sense and transduce environmental cues and presynaptic signals, respectively. Despite their unique cellular roles, both compartments exhibit remarkable parallels in the general principles, as well as molecular mechanisms, by which their protein composition, membrane domain architecture, cellular interactions, and structural and functional plasticity are regulated. We compare and contrast the pathways required for the generation and function of cilia and dendritic spines, and suggest that insights from the study of one may inform investigations into the other of these critically important signaling structures.


Assuntos
Cílios/fisiologia , Espinhas Dendríticas/fisiologia , Animais , Citoesqueleto/fisiologia , Humanos , Plasticidade Neuronal , Transdução de Sinais , Transmissão Sináptica
8.
J Cell Biol ; 196(3): 345-62, 2012 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-22312004

RESUMO

Transcription factors are essential for regulating neuronal microtubules (MTs) during development and after axon damage. In this paper, we identify a novel neuronal function for Drosophila melanogaster FoxO in limiting MT stability at the neuromuscular junction (NMJ). foxO loss-of-function NMJs displayed augmented MT stability. In contrast, motor neuronal overexpression of wild-type FoxO moderately destabilized MTs, whereas overexpression of constitutively nuclear FoxO severely destabilized MTs. Thus, FoxO negatively regulates synaptic MT stability. FoxO family members are well-established components of stress-activated feedback loops. We hypothesized that FoxO might also be regulated by cytoskeletal stress because it was well situated to shape neuronal MT organization after cytoskeletal damage. Indeed, levels of neuronal FoxO were strongly reduced after acute pharmacological MT disruption as well as sustained genetic disruption of the neuronal cytoskeleton. This decrease was independent of the dual leucine zipper kinase-Wallenda pathway and required function of Akt kinase. We present a model wherein FoxO degradation is a component of a stabilizing, protective response to cytoskeletal insult.


Assuntos
Proteínas de Drosophila/genética , Fatores de Transcrição Forkhead/genética , Microtúbulos/metabolismo , Animais , Citoesqueleto/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Embrião não Mamífero/metabolismo , Imunofluorescência , Fatores de Transcrição Forkhead/metabolismo , Neurônios Motores/metabolismo , Mutação
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