Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
bioRxiv ; 2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38187727

RESUMO

Single-nucleotide polymorphisms (SNPs) in forkhead box protein P2 (FOXP2) and oxytocin receptor (OXTR) genes have been associated with linguistic and social development in humans, as well as to symptom severity in autism spectrum disorder (ASD). Studying biobehavioral mechanisms in the species most closely related to humans can provide insights into the origins of human communication, and the impact of genetic variation on complex behavioral phenotypes. Here, we aimed to determine if bonobos (Pan paniscus) exhibit individual variation in FOXP2 and OXTR loci that have been associated with human social development and behavior. Although the ASD-related variants were reported in 13-41% of the human population, we did not find variation at these loci in our sample of 13 bonobos. However, we did identify a novel variant in bonobo FOXP2, as well as four novel variants in bonobo OXTR that were 17-184 base pairs from the human ASD variants. We also found the same linked, homozygous allelic combination across the 4 novel OXTR SNPs (homozygous TGTC) in 6 of the 13 bonobos, indicating that this combination may be under positive selection. When comparing the combined OXTR genotypes, we found significant group differences in social behavior; bonobos with zero copies of the TGTC combination were less social than bonobos with one copy of the TGTC combination. Taken together, our findings suggest that these OXTR variants may influence individual-level social behavior in bonobos and support the notion that linked genetic variants are promising risk factors for social communication deficits in humans.

2.
G3 (Bethesda) ; 10(9): 3071-3085, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32601060

RESUMO

Identifying the mechanisms behind neuronal fate specification are key to understanding normal neural development in addition to neurodevelopmental disorders such as autism and schizophrenia. In vivo cell fate specification is difficult to study in vertebrates. However, the nematode Caenorhabditis elegans, with its invariant cell lineage and simple nervous system of 302 neurons, is an ideal organism to explore the earliest stages of neural development. We used a comparative transcriptome approach to examine the role of cnd-1/NeuroD1 in C. elegans nervous system development and function. This basic helix-loop-helix transcription factor is deeply conserved across phyla and plays a crucial role in cell fate specification in both the vertebrate nervous system and pancreas. We find that cnd-1 controls expression of ceh-5, a Vax2-like homeobox class transcription factor, in the RME head motorneurons and PVQ tail interneurons. We also show that cnd-1 functions redundantly with the Hox gene ceh-13/labial in defining the fate of DD1 and DD2 embryonic ventral nerve cord motorneurons. These data highlight the utility of comparative transcriptomes for identifying transcription factor targets and understanding gene regulatory networks.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas do Tecido Nervoso , Neurônios/metabolismo
3.
G3 (Bethesda) ; 10(6): 1949-1962, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32273286

RESUMO

Proper nervous system development is required for an organism's survival and function. Defects in neurogenesis have been linked to neurodevelopmental disorders such as schizophrenia and autism. Understanding the gene regulatory networks that orchestrate neural development, specifically cascades of proneural transcription factors, can better elucidate which genes are most important during early neurogenesis. Neurogenins are a family of deeply conserved factors shown to be both necessary and sufficient for the development of neural subtypes. However, the immediate downstream targets of neurogenin are not well characterized. The objective of this study was to further elucidate the role of ngn-1/neurogenin in nervous system development and to identify its downstream transcriptional targets, using the nematode Caenorhabditis elegans as a model for this work. We found that ngn-1 is required for axon outgrowth, nerve ring architecture, and neuronal cell fate specification. We also showed that ngn-1 may have roles in neuroblast migration and epithelial integrity during embryonic development. Using RNA sequencing and comparative transcriptome analysis, we identified eight transcription factors (hlh-34/NPAS1, unc-42/PROP1, ceh-17/PHOX2A, lim-4/LHX6, fax-1/NR2E3, lin-11/LHX1, tlp-1/ZNF503, and nhr-23/RORB) whose transcription is activated, either directly or indirectly, by ngn-1 Our results show that ngn-1 has a role in transcribing known terminal regulators that establish and maintain cell fate of differentiated neural subtypes and confirms that ngn-1 functions as a proneural transcription factor in C. elegans neurogenesis.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética
4.
Development ; 143(7): 1182-91, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26903502

RESUMO

During development of the nervous system, growing axons rely on guidance molecules to direct axon pathfinding. A well-characterized family of guidance molecules are the membrane-associated ephrins, which together with their cognate Eph receptors, direct axon navigation in a contact-mediated fashion. InC. elegans, the ephrin-Eph signaling system is conserved and is best characterized for their roles in neuroblast migration during early embryogenesis. This study demonstrates a role for the C. elegans ephrin EFN-4 in axon guidance. We provide both genetic and biochemical evidence that is consistent with the C. elegans divergent L1 cell adhesion molecule LAD-2 acting as a non-canonical ephrin receptor to EFN-4 to promote axon guidance. We also show that EFN-4 probably functions as a diffusible factor because EFN-4 engineered to be soluble can promote LAD-2-mediated axon guidance. This study thus reveals a potential additional mechanism for ephrins in regulating axon guidance and expands the repertoire of receptors by which ephrins can signal.


Assuntos
Axônios/metabolismo , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/embriologia , Efrinas/genética , Sistema Nervoso/embriologia , Molécula L1 de Adesão de Célula Nervosa/genética , Neurogênese/fisiologia , Animais , Linhagem Celular , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Morfogênese , Receptores da Família Eph/genética , Transdução de Sinais
5.
Genetics ; 202(2): 639-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26645816

RESUMO

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body-wall muscle and in parallel with HS modification genes and HSPG core proteins. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system.


Assuntos
Axônios/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Efrinas/genética , Efrinas/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Animais , Linhagem Celular , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Interneurônios/metabolismo , Modelos Biológicos , Neurônios Motores/metabolismo , Mutação , Neurogênese/genética , Neurônios/metabolismo , Fenótipo , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Transdução de Sinais
6.
PLoS One ; 10(5): e0121397, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25938228

RESUMO

BACKGROUND: The C. elegans proteins PTP-3/LAR-RPTP and SDN-1/Syndecan are conserved cell adhesion molecules. Loss-of-function (LOF) mutations in either ptp-3 or sdn-1 result in low penetrance embryonic developmental defects. Work from other systems has shown that syndecans can function as ligands for LAR receptors in vivo. We used double mutant analysis to test whether ptp-3 and sdn-1 function in a linear genetic pathway during C. elegans embryogenesis. RESULTS: We found animals with LOF in both sdn-1 and ptp-3 exhibited a highly penetrant synthetic lethality (SynLet), with only a small percentage of animals surviving to adulthood. Analysis of the survivors demonstrated that these animals had a synergistic increase in the penetrance of embryonic developmental defects. Together, these data strongly suggested PTP-3 and SDN-1 function in parallel during embryogenesis. We subsequently used RNAi to knockdown ~3,600 genes predicted to encode secreted and/or transmembrane molecules to identify genes that interacted with ptp-3 or sdn-1. We found that the Wnt ligand, lin-44, was SynLet with sdn-1, but not ptp-3. We used 4-dimensional time-lapse analysis to characterize the interaction between lin-44 and sdn-1. We found evidence that loss of lin-44 caused defects in the polarization and migration of endodermal precursors during gastrulation, a previously undescribed role for lin-44 that is strongly enhanced by the loss of sdn-1. CONCLUSIONS: PTP-3 and SDN-1 function in compensatory pathways during C. elegans embryonic and larval development, as simultaneous loss of both genes has dire consequences for organismal survival. The Wnt ligand lin-44 contributes to the early stages of gastrulation in parallel to sdn-1, but in a genetic pathway with ptp-3. Overall, the SynLet phenotype provides a robust platform to identify ptp-3 and sdn-1 interacting genes, as well as other genes that function in development, yet might be missed in traditional forward genetic screens.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Desenvolvimento Embrionário , Testes Genéticos , Glicoproteínas/metabolismo , Animais , Caenorhabditis elegans/genética , Moléculas de Adesão Celular/metabolismo , Embrião não Mamífero/metabolismo , Epiderme/metabolismo , Gastrulação , Genes de Helmintos , Genótipo , Proteínas de Fluorescência Verde/metabolismo , Larva/metabolismo , Ligantes , Mutação/genética , Penetrância , Fenótipo , Interferência de RNA
7.
Neuron ; 61(6): 865-79, 2009 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-19323996

RESUMO

Homeostatic sensory systems detect small deviations in temperature, water balance, pH, and energy needs to regulate adaptive behavior and physiology. In C. elegans, a homeostatic preference for intermediate oxygen (O2) levels requires cGMP signaling through soluble guanylate cyclases (sGCs), proteins that bind gases through an associated heme group. Here we use behavioral analysis, functional imaging, and genetics to show that reciprocal changes in O2 levels are encoded by sensory neurons that express alternative sets of sGCs. URX sensory neurons are activated by increases in O2 levels, and require the sGCs gcy-35 and gcy-36. BAG sensory neurons are activated by decreases in O2 levels, and require the sGCs gcy-31 and gcy-33. The sGCs are instructive O2 sensors, as forced expression of URX sGC genes causes BAG neurons to detect O2 increases. Both sGC expression and cell-intrinsic dynamics contribute to the differential roles of URX and BAG in O2-dependent behaviors.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Guanilato Ciclase/classificação , Guanilato Ciclase/metabolismo , Oxigênio/metabolismo , Células Receptoras Sensoriais/classificação , Células Receptoras Sensoriais/fisiologia , Animais , Comportamento Animal , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Guanilato Ciclase/genética , Luz , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Mutação , Compostos Organometálicos/metabolismo , Oxigênio/farmacologia , Fenantrolinas/metabolismo , Inanição/metabolismo
8.
Development ; 135(16): 2747-2756, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18614580

RESUMO

The F-spondin family of extracellular matrix proteins has been implicated in axon outgrowth, fasciculation and neuronal cell migration, as well as in the differentiation and proliferation of non-neuronal cells. In screens for mutants defective in C. elegans embryonic morphogenesis, we identified SPON-1, the only C. elegans member of the spondin family. SPON-1 is synthesized in body muscles and localizes to integrin-containing structures on body muscles and to other basement membranes. SPON-1 maintains strong attachments of muscles to epidermis; in the absence of SPON-1, muscles progressively detach from the epidermis, causing defective epidermal elongation. In animals with reduced integrin function, SPON-1 becomes dose dependent, suggesting that SPON-1 and integrins function in concert to promote the attachment of muscles to the basement membrane. Although spon-1 mutants display largely normal neurite outgrowth, spon-1 synergizes with outgrowth defective mutants, revealing a cryptic role for SPON-1 in axon extension. In motoneurons, SPON-1 acts in axon guidance and fasciculation, whereas in interneurons SPON-1 maintains process position. Our results show that a spondin maintains cell-matrix adhesion in multiple tissues.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/fisiologia , Proteínas da Matriz Extracelular/fisiologia , Sistema Nervoso/embriologia , Sequência de Aminoácidos , Animais , Axônios/fisiologia , Membrana Basal/fisiologia , Caenorhabditis elegans/embriologia , Proteínas de Caenorhabditis elegans/genética , Adesão Celular , Proteínas da Matriz Extracelular/genética , Integrinas/fisiologia , Dados de Sequência Molecular , Morfogênese/fisiologia , Neurônios Motores/fisiologia , Músculos/fisiologia , Mutação , Sistema Nervoso/metabolismo , Neuritos/fisiologia
9.
Genetics ; 176(3): 1591-607, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17507686

RESUMO

Semaphorins are extracellular proteins that regulate axon guidance and morphogenesis by interacting with a variety of cell surface receptors. Most semaphorins interact with plexin-containing receptor complexes, although some interact with non-plexin receptors. Class 2 semaphorins are secreted molecules that control axon guidance and epidermal morphogenesis in Drosophila and Caenorhabditis elegans. We show that the C. elegans class 2 semaphorin MAB-20 binds the plexin PLX-2. plx-2 mutations enhance the phenotypes of hypomorphic mab-20 alleles but not those of mab-20 null alleles, indicating that plx-2 and mab-20 act in a common pathway. Both mab-20 and plx-2 mutations affect epidermal morphogenesis during embryonic and in postembryonic development. In both contexts, plx-2 null mutant phenotypes are much less severe than mab-20 null phenotypes, indicating that PLX-2 is not essential for MAB-20 signaling. Mutations in the ephrin efn-4 do not synergize with mab-20, indicating that EFN-4 may act in MAB-20 signaling. EFN-4 and PLX-2 are coexpressed in the late embryonic epidermis where they play redundant roles in MAB-20-dependent cell sorting.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Moléculas de Adesão Celular/fisiologia , Efrina-A4/fisiologia , Proteínas de Membrana/metabolismo , Morfogênese , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Semaforinas/metabolismo , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Transdução de Sinais
10.
Dev Biol ; 294(2): 352-65, 2006 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-16677626

RESUMO

The anosmin-1 protein family regulates cell migration, axon guidance, and branching, by mechanisms that are not well understood. We show that the C. elegans anosmin-1 ortholog KAL-1 promotes migrations of ventral neuroblasts prior to epidermal enclosure. KAL-1 does not modulate FGF signaling in neuroblast migration and acts in parallel to other neuroblast migration pathways. Defects in heparan sulfate (HS) synthesis or in specific HS modifications disrupt neuroblast migrations and affect the KAL-1 pathway. KAL-1 binds the cell surface HS proteoglycans syndecan/SDN-1 and glypican/GPN-1. This interaction is mediated via HS side chains and requires specific HS modifications. SDN-1 and GPN-1 are expressed in ventral neuroblasts and have redundant roles in KAL-1-dependent neuroblast migrations. Our findings suggest that KAL-1 interacts with multiple HSPGs to promote cell migration.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Movimento Celular/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteoglicanas/metabolismo , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Sequência de Carboidratos , Proteínas da Matriz Extracelular/genética , Proteoglicanas de Heparan Sulfato/genética , Heparitina Sulfato/metabolismo , Humanos , Síndrome de Kallmann , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Fenótipo , Proteoglicanas/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Sindecanas
11.
J Neurosci ; 25(33): 7517-28, 2005 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-16107639

RESUMO

Leukocyte-common antigen related (LAR)-like phosphatase receptors are conserved cell adhesion molecules that function in multiple developmental processes. The Caenorhabditis elegans ptp-3 gene encodes two LAR family isoforms that differ in the extracellular domain. We show here that the long isoform, PTP-3A, localizes specifically at synapses and that the short isoform, PTP-3B, is extrasynaptic. Mutations in ptp-3 cause defects in axon guidance that can be rescued by PTP-3B but not by PTP-3A. Mutations that specifically affect ptp-3A do not affect axon guidance but instead cause alterations in synapse morphology. Genetic double-mutant analysis is consistent with ptp-3A acting with the extracellular matrix component nidogen, nid-1, and the intracellular adaptor alpha-liprin, syd-2. nid-1 and syd-2 are required for the recruitment and stability of PTP-3A at synapses, and mutations in ptp-3 or nid-1 result in aberrant localization of SYD-2. Overexpression of PTP-3A is able to bypass the requirement for nid-1 for the localization of SYD-2 and RIM. We propose that PTP-3A acts as a molecular link between the extracellular matrix and alpha-liprin during synaptogenesis.


Assuntos
Axônios/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/enzimologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas Tirosina Fosfatases/biossíntese , Receptores de Superfície Celular/biossíntese , Sinapses/metabolismo , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Caenorhabditis elegans/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Receptores de Superfície Celular/genética , Sinapses/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...