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1.
Nat Microbiol ; 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39438720

RESUMO

Microorganisms use toxins to kill competing microorganisms or eukaryotic cells. Polymorphic toxins are proteins that encode carboxy-terminal toxin domains. Here we developed a computational approach to identify previously undiscovered, conserved toxin domains of polymorphic toxins within 105,438 microbial genomes. We validated nine short toxins, showing that they cause cell death upon heterologous expression in either Escherichia coli or Saccharomyces cerevisiae. Five cognate immunity genes that neutralize the toxins were also discovered. The toxins are encoded by 2.2% of sequenced bacteria. A subset of the toxins exhibited potent antifungal activity against various pathogenic fungi but not against two invertebrate model organisms or macrophages. Experimental validation suggested that these toxins probably target the cell membrane or DNA or inhibit cell division. Further characterization and structural analysis of two toxin-immunity protein complexes confirmed DNase activity. These findings expand our knowledge of microbial toxins involved in inter-microbial competition that may have the potential for clinical and biotechnological applications.

2.
Nat Commun ; 15(1): 4273, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769103

RESUMO

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we create a comprehensive gene expression atlas of pure populations of hermaphrodites and males of the nematode Caenorhabditis elegans across development. We discover numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and G protein-coupled receptors. We identify INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually dimorphic roles in various behaviors, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans. Furthermore, it highlights conserved genes that may underlie the sexually dimorphic manifestation of different human diseases.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Caracteres Sexuais , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Masculino , Feminino , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Células Receptoras Sensoriais/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Perfilação da Expressão Gênica
3.
Nat Methods ; 21(7): 1275-1287, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38811857

RESUMO

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.


Assuntos
Neurônios , Optogenética , Optogenética/métodos , Animais , Neurônios/fisiologia , Neurônios/metabolismo , Transmissão Sináptica , Opsinas/genética , Opsinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Camundongos , Humanos , Sinapses/fisiologia , Sinapses/metabolismo
4.
APL Bioeng ; 8(2): 026104, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38655543

RESUMO

The correct interpretation of threat and reward is important for animal survival. Often, the decisions underlying these behavioral programs are mediated by volatile compounds in the animal's environment, which they detect and discriminate with specialized olfactory neurons along their body. Caenorhabditis (C.) elegans senses chemical stimuli with neurons located in the head and the tail of the animal, which mediate either attractive or aversive behaviors. How conflicting stimuli are processed in animals navigating different chemical gradients is poorly understood. Here, we conceived, created, and capitalized on a novel microfluidic device to enable automated and precise stimulation of head and tail neurons, either simultaneously or sequentially, while reading out neuronal activity in sensory and interneurons using genetically encoded calcium indicators. We achieve robust and programmable chemical pulses through the modulation of inlet pressures. To evaluate the device performance, we synchronized the flow control with microscopy data acquisition and characterized the flow properties in the fabricated devices. Together, our design has the potential to provide insight into the neural circuits and behavior of C. elegans simulating the experience of natural environments.

5.
Nat Commun ; 14(1): 7066, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37923706

RESUMO

Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.


Assuntos
Mutação com Ganho de Função , Chaperonas Moleculares , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Dobramento de Proteína , Proteínas do Tecido Nervoso/genética
6.
Cell Rep ; 42(9): 113075, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37691148

RESUMO

The capacity of animals to respond to hazardous stimuli in their surroundings is crucial for their survival. In mammals, complex evaluations of the environment require large numbers and different subtypes of neurons. The nematode C. elegans avoids hazardous chemicals they encounter by reversing their direction of movement. How does the worms' compact nervous system process the spatial information and direct motion change? We show here that a single interneuron, AVA, receives glutamatergic excitatory and inhibitory signals from head and tail sensory neurons, respectively. AVA integrates the spatially distinct and opposing cues, whose output instructs the animal's behavioral decision. We further find that the differential activation of AVA stems from distinct localization of inhibitory and excitatory glutamate-gated receptors along AVA's process and from different threshold sensitivities of the sensory neurons. Our results thus uncover a cellular mechanism that mediates spatial computation of nociceptive cues for efficient decision-making in C. elegans.

7.
Curr Opin Neurobiol ; 82: 102757, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37572555

RESUMO

Many animal behaviors are manifested differently in the two sexes of a given species, but how such sexual dimorphism is imprinted in the nervous system is not always clear. One mechanism involved is synaptic dimorphism, by which the same neurons exist in the two sexes, but form synapses that differ in features such as anatomy, molecular content or fate. While some evidence for synaptic dimorphism exists in humans and mammals, identifying these mechanisms in invertebrates has proven simpler, due to their smaller nervous systems and absence of external regulation by sex hormones. This review aims to present the current status of the field in invertebrates, the available toolkit for the study of synaptic dimorphism, and the standing questions that still remain incompletely answered.


Assuntos
Invertebrados , Caracteres Sexuais , Animais , Humanos , Neurônios/fisiologia , Sinapses/fisiologia , Mamíferos
8.
FEBS J ; 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36582142

RESUMO

Dimorphic traits, shaped by both natural and sexual selection, ensure optimal fitness and survival of the organism. This includes neuronal circuits that are largely affected by different experiences and environmental conditions. Recent evidence suggests that sexual dimorphism of neuronal circuits extends to different levels such as neuronal activity, connectivity and molecular topography that manifest in response to various experiences, including chemical exposures, starvation and stress. In this review, we propose some common principles that govern experience-dependent sexually dimorphic circuits in both vertebrate and invertebrate organisms. While sexually dimorphic neuronal circuits are predetermined, they have to maintain a certain level of fluidity to be adaptive to different experiences. The first layer of dimorphism is at the level of the neuronal circuit, which appears to be dictated by sex-biased transcription factors. This could subsequently lead to differences in the second layer of regulation namely connectivity and synaptic properties. The third regulator of experience-dependent responses is the receptor level, where dimorphic expression patterns determine the primary sensory encoding. We also highlight missing pieces in this field and propose future directions that can shed light onto novel aspects of sexual dimorphism with potential benefits to sex-specific therapeutic approaches. Thus, sexual identity and experience simultaneously determine behaviours that ultimately result in the maximal survival success.

9.
Nat Commun ; 13(1): 6825, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369281

RESUMO

How sensory perception is processed by the two sexes of an organism is still only partially understood. Despite some evidence for sexual dimorphism in auditory and olfactory perception, whether touch is sensed in a dimorphic manner has not been addressed. Here we find that the neuronal circuit for tail mechanosensation in C. elegans is wired differently in the two sexes and employs a different combination of sex-shared sensory neurons and interneurons in each sex. Reverse genetic screens uncovered cell- and sex-specific functions of the alpha-tubulin mec-12 and the sodium channel tmc-1 in sensory neurons, and of the glutamate receptors nmr-1 and glr-1 in interneurons, revealing the underlying molecular mechanisms that mediate tail mechanosensation. Moreover, we show that only in males, the sex-shared interneuron AVG is strongly activated by tail mechanical stimulation, and accordingly is crucial for their behavioral response. Importantly, sex reversal experiments demonstrate that the sexual identity of AVG determines both the behavioral output of the mechanosensory response and the molecular pathways controlling it. Our results present extensive sexual dimorphism in a mechanosensory circuit at both the cellular and molecular levels.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Masculino , Feminino , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Interneurônios/metabolismo , Células Receptoras Sensoriais/metabolismo , Caracteres Sexuais , Canais Iônicos/genética , Canais Iônicos/metabolismo
10.
Curr Biol ; 32(20): 4372-4385.e7, 2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36075218

RESUMO

The effect of the detailed connectivity of a neural circuit on its function and the resulting behavior of the organism is a key question in many neural systems. Here, we study the circuit for nociception in C. elegans, which is composed of the same neurons in the two sexes that are wired differently. We show that the nociceptive sensory neurons respond similarly in the two sexes, yet the animals display sexually dimorphic behaviors to the same aversive stimuli. To uncover the role of the downstream network topology in shaping behavior, we learn and simulate network models that replicate the observed dimorphic behaviors and use them to predict simple network rewirings that would switch behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Interestingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that network topologies that enable efficient avoidance of noxious cues have a reproductive "cost." Our results present a deconstruction of the design of a neural circuit that controls sexual behavior and how to reprogram it.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Masculino , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Nociceptividade , Sistema Nervoso , Células Receptoras Sensoriais/fisiologia
12.
Curr Top Dev Biol ; 144: 245-268, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33992155

RESUMO

Sex-specific behaviors are common in nature and are crucial for reproductive fitness and species survival. A key question in the field of sex/gender neurobiology is whether and to what degree the sex-shared nervous system differs between the sexes in the anatomy, connectivity and molecular identity of its components. An equally intriguing issue is how does the same sex-shared neuronal template diverge to mediate distinct behavioral outputs in females and males. This chapter aims to present the most up-to-date understanding of how this task is achieved in C. elegans. The vast majority of neurons in C. elegans are shared among the two sexes in terms of their lineage history, anatomical position and neuronal identity. Yet a substantial amount of evidence points to the hermaphrodite-male counterparts of some neurons expressing different genes and forming different synaptic connections. This, in turn, enables the same cells and circuits to transmit discrete signals in the two sexes and ultimately execute different functions. We review the various sex-shared behavioral paradigms that have been shown to be sexually dimorphic in recent years, discuss the mechanisms that underlie these examples, refer to the developmental regulation of neuronal dimorphism and suggest evolutionary concepts that emerge from the data.


Assuntos
Caenorhabditis elegans , Sistema Nervoso , Caracteres Sexuais , Animais , Caenorhabditis elegans/genética , Feminino , Aptidão Genética , Masculino , Neurobiologia , Neurônios
13.
Elife ; 92020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021200

RESUMO

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but previously uncharacterized Doublesex/Mab-3 related transcription factor (DMRT), dmd-4, is expressed in two classes of sex-shared phasmid neurons specifically in hermaphrodites but not in males. We find dmd-4 to promote hermaphrodite-specific synaptic connectivity and neuronal function of phasmid sensory neurons. Sex-specificity of DMD-4 function is conferred by a novel mode of posttranslational regulation that involves sex-specific protein stabilization through ubiquitin binding to a phylogenetically conserved but previously unstudied protein domain, the DMA domain. A human DMRT homolog of DMD-4 is controlled in a similar manner, indicating that our findings may have implications for the control of sexual differentiation in other animals as well.


Assuntos
Proteínas de Caenorhabditis elegans , Neurônios/metabolismo , Caracteres Sexuais , Fatores de Transcrição , Ubiquitina/metabolismo , Animais , Comportamento Animal , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Transtornos do Desenvolvimento Sexual , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Transmissão Sináptica/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Curr Biol ; 30(21): 4128-4141.e5, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32857970

RESUMO

Sexually dimorphic circuits underlie behavioral differences between the sexes, yet the molecular mechanisms involved in their formation are poorly understood. We show here that sexually dimorphic connectivity patterns arise in C. elegans through local ubiquitin-mediated protein degradation in selected synapses of one sex but not the other. Specifically, synaptic degradation occurs via binding of the evolutionary conserved E3 ligase SEL-10/FBW7 to a phosphodegron binding site of the netrin receptor UNC-40/DCC (Deleted in Colorectal Cancer), resulting in degradation of UNC-40. In animals carrying an undegradable unc-40 gain-of-function allele, synapses were retained in both sexes, compromising the activity of the circuit without affecting neurite guidance. Thus, by decoupling the synaptic and guidance functions of the netrin pathway, we reveal a critical role for dimorphic protein degradation in controlling neuronal connectivity and activity. Additionally, the interaction between SEL-10 and UNC-40 is necessary not only for sex-specific synapse pruning, but also for other synaptic functions. These findings provide insight into the mechanisms that generate sex-specific differences in neuronal connectivity, activity, and function.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Caracteres Sexuais , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Axônios/metabolismo , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Moléculas de Adesão Celular/genética , Mutação com Ganho de Função , Masculino , Proteólise , Ubiquitinação/genética
15.
Annu Rev Neurosci ; 42: 365-383, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-30939099

RESUMO

The structural and functional properties of neurons have intrigued scientists since the pioneering work of Santiago Ramón y Cajal. Since then, emerging cutting-edge technologies, including light and electron microscopy, electrophysiology, biochemistry, optogenetics, and molecular biology, have dramatically increased our understanding of dendritic properties. This advancement was also facilitated by the establishment of different animal model organisms, from flies to mammals. Here we describe the emerging model system of a Caenorhabditis elegans polymodal neuron named PVD, whose dendritic tree follows a stereotypical structure characterized by repeating candelabra-like structural units. In the past decade, progress has been made in understanding PVD's functions, morphogenesis, regeneration, and aging, yet many questions still remain.


Assuntos
Envelhecimento , Dendritos/patologia , Neurônios/patologia , Regeneração/fisiologia , Animais , Caenorhabditis elegans/fisiologia , Humanos , Células Receptoras Sensoriais
16.
Development ; 144(13): 2364-2374, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28576774

RESUMO

The aging brain undergoes structural changes that affect brain homeostasis, neuronal function and consequently cognition. The complex architecture of dendritic arbors poses a challenge to understanding age-dependent morphological alterations, behavioral plasticity and remodeling following brain injury. Here, we use the PVD polymodal neurons of C. elegans as a model to study how aging affects neuronal plasticity. Using confocal live imaging of C. elegans PVD neurons, we demonstrate age-related progressive morphological alterations of intricate dendritic arbors. We show that mutations in daf-2, which encodes an insulin-like growth factor receptor ortholog, fail to inhibit the progressive morphological aging of dendrites and do not prevent the minor decline in response to harsh touch during aging. We uncovered that PVD aging is characterized by a major decline in the regenerative potential of dendrites following experimental laser dendrotomy. Furthermore, the remodeling of transected dendritic trees by AFF-1-mediated self-fusion can be restored in old animals by daf-2 mutations, and can be differentially re-established by ectopic expression of the fusion protein AFF-1. Thus, ectopic expression of the fusogen AFF-1 in the PVD and mutations in daf-2 differentially rejuvenate some aspects of dendritic regeneration following injury.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Dendritos/metabolismo , Regeneração , Envelhecimento/metabolismo , Animais , Fusão Celular , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Larva/metabolismo , Modelos Biológicos , Mutação/genética , Transdução de Sinais
17.
Genetics ; 206(1): 215-230, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28283540

RESUMO

Injury triggers regeneration of axons and dendrites. Research has identified factors required for axonal regeneration outside the CNS, but little is known about regeneration triggered by dendrotomy. Here, we study neuronal plasticity triggered by dendrotomy and determine the fate of complex PVD arbors following laser surgery of dendrites. We find that severed primary dendrites grow toward each other and reconnect via branch fusion. Simultaneously, terminal branches lose self-avoidance and grow toward each other, meeting and fusing at the tips via an AFF-1-mediated process. Ectopic branch growth is identified as a step in the regeneration process required for bypassing the lesion site. Failure of reconnection to the severed dendrites results in degeneration of the distal end of the neuron. We discover pruning of excess branches via EFF-1 that acts to recover the original wild-type arborization pattern in a late stage of the process. In contrast, AFF-1 activity during dendritic auto-fusion is derived from the lateral seam cells and not autonomously from the PVD neuron. We propose a model in which AFF-1-vesicles derived from the epidermal seam cells fuse neuronal dendrites. Thus, EFF-1 and AFF-1 fusion proteins emerge as new players in neuronal arborization and maintenance of arbor connectivity following injury in Caenorhabditis elegans Our results demonstrate that there is a genetically determined multi-step pathway to repair broken dendrites in which EFF-1 and AFF-1 act on different steps of the pathway. EFF-1 is essential for dendritic pruning after injury and extrinsic AFF-1 mediates dendrite fusion to bypass injuries.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Glicoproteínas de Membrana/genética , Regeneração/genética , Animais , Animais Geneticamente Modificados , Axônios/metabolismo , Axônios/patologia , Caenorhabditis elegans/crescimento & desenvolvimento , Dendritos/genética , Dendritos/patologia , Plasticidade Neuronal/genética , Células Receptoras Sensoriais/metabolismo
18.
Curr Biol ; 27(2): 199-209, 2017 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-28065609

RESUMO

Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neuron pair of the nematode C. elegans differentiates in a strikingly sex-specific manner. In hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, but in males PHC differentiates into a densely connected hub sensory neuron/interneuron, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We show that the differentiation into such a hub neuron involves the sex-specific scaling of several components of the synaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology, and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured by its collaboration with non-sex-specific terminal selector-type transcription factors, whereas the sex specificity of dmd-3 action is ensured by the hermaphrodite-specific transcriptional master regulator of hermaphroditic cell identity tra-1, which represses the transcription of dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Diferenciação Celular , Neurônios/citologia , Fatores de Transcrição/metabolismo , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Neurônios/fisiologia , Caracteres Sexuais , Diferenciação Sexual , Sinapses/fisiologia , Fatores de Transcrição/genética
19.
Nature ; 533(7602): 206-11, 2016 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-27144354

RESUMO

Whether and how neurons that are present in both sexes of the same species can differentiate in a sexually dimorphic manner is not well understood. A comparison of the connectomes of the Caenorhabditis elegans hermaphrodite and male nervous systems reveals the existence of sexually dimorphic synaptic connections between neurons present in both sexes. Here we demonstrate sex-specific functions of these sex-shared neurons and show that many neurons initially form synapses in a hybrid manner in both the male and hermaphrodite pattern before sexual maturation. Sex-specific synapse pruning then results in the sex-specific maintenance of subsets of these connections. Reversal of the sexual identity of either the pre- or postsynaptic neuron alone transforms the patterns of synaptic connectivity to that of the opposite sex. A dimorphically expressed and phylogenetically conserved transcription factor is both necessary and sufficient to determine sex-specific connectivity patterns. Our studies reveal new insights into sex-specific circuit development.


Assuntos
Caenorhabditis elegans/citologia , Plasticidade Neuronal/fisiologia , Células Receptoras Sensoriais/citologia , Caracteres Sexuais , Sinapses/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Sequência Conservada , Proteínas de Ligação a DNA , Transtornos do Desenvolvimento Sexual , Proteínas de Drosophila , Feminino , Masculino , Plasticidade Neuronal/genética , Células Receptoras Sensoriais/metabolismo , Maturidade Sexual/genética , Maturidade Sexual/fisiologia , Fatores de Transcrição/metabolismo
20.
Curr Biol ; 22(19): 1774-82, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22921367

RESUMO

BACKGROUND: The molecular mechanisms that determine axonal growth potential are poorly understood. Intrinsic growth potential decreases with age, and thus one strategy to identify molecular pathways controlling intrinsic growth potential is by studying developing young neurons. The programmed and stereotypic remodeling of Drosophila mushroom body (MB) neurons during metamorphosis offers a unique opportunity to uncover such mechanisms. Despite emerging insights into MB γ-neuron axon pruning, nothing is known about the ensuing axon re-extension. RESULTS: Using mosaic loss of function, we found that the nuclear receptor UNF (Nr2e3) is cell autonomously required for the re-extension of MB γ-axons following pruning, but not for the initial growth or guidance of any MB neuron type. We found that UNF promotes this process of developmental axon regrowth via the TOR pathway as well as a late axon guidance program via an unknown mechanism. We have thus uncovered a novel developmental program of axon regrowth that is cell autonomously regulated by the UNF nuclear receptor and the TOR pathway. CONCLUSIONS: Our results suggest that UNF activates neuronal re-extension during development. Taken together, we show that axon growth during developmental remodeling is mechanistically distinct from initial axon outgrowth. Due to the involvement of the TOR pathway in axon regeneration following injury, our results also suggests that developmental regrowth shares common molecular mechanisms with regeneration following injury.


Assuntos
Axônios/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Regeneração Nervosa/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Metamorfose Biológica/fisiologia , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Corpos Pedunculados/fisiologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Receptores Citoplasmáticos e Nucleares/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
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