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Oliver Hobert

Publications and source records attributed to Oliver Hobert.

At least 37 records · Page 2Linked to original sources
PubMed2004

Differential functions of the C. elegans FGF receptor in axon outgrowth and maintenance of axon position.

Wiring of the nervous system requires that axons navigate to their targets and maintain their correct positions in axon fascicles after termination of axon outgrowth. We show here that the C. elegans fibroblast growth factor receptor (FGFR), EGL-15, affects both processes in fundamentally distinct manners. FGF-dependent activation of the EGL-15 tyrosine kinase and subsequently the GTPase LET-60/ras is required within epidermal cells, the substratum for most outgrowing axon, for appropriate outgrowth of specific axon classes to their target area. In contrast, genetic elimination of the FGFR isoform EGL-15(5A), defined by the inclusion of an alternative extracellular interimmunoglobulin domain, has no consequence for axon outgrowth but leads to a failure to postembryonically maintain axon position within defined axon fascicles. An engineered, secreted form of EGL-15(5A) containing only its ectodomain is sufficient for maintenance of axon position, thus providing novel insights into receptor tyrosine kinase function and the process of maintaining axon position.

Animals↗
PubMed2004

CisOrtho: a program pipeline for genome-wide identification of transcription factor target genes using phylogenetic footprinting.

BACKGROUND: All known genomes code for a large number of transcription factors. It is important to develop methods that will reveal how these transcription factors act on a genome wide level, that is, through what target genes they exert their function. RESULTS: We describe here a program pipeline aimed at identifying transcription factor target genes in whole genomes. Starting from a consensus binding site, represented as a weight matrix, potential sites in a pre-filtered genome are identified and then further filtered by assessing conservation of the putative site in the genome of a related species, a process called phylogenetic footprinting. CisOrtho has been successfully used to identify targets for two homeodomain transcription factors in the genomes of the nematodes Caenorhabditis elegans and Caenorhabditis briggsae. CONCLUSIONS: CisOrtho will identify targets of other nematode transcription factors whose DNA binding specificity is known and can be easily adapted to search other genomes for transcription factor targets.

Animals↗
PubMed2004

Differential sulfations and epimerization define heparan sulfate specificity in nervous system development.

Heparan sulfate proteoglycans (HSPG) are components of the extracellular matrix through which axons navigate to reach their targets. The heparan sulfate (HS) side chains of HSPGs show complex and differentially regulated patterns of secondary modifications, including sulfations of distinct hydroxyl groups and epimerization of an asymmetric carbon atom. These modifications endow the HSPG-containing extracellular matrix with the potential to code for an enormous molecular diversity. Attempting to decode this diversity, we analyzed C. elegans animals lacking three HS-modifying enzymes, glucuronyl C5-epimerase, heparan 6O-sulfotransferase, and 2O-sulfotransferase. Each of the mutant animals exhibit distinct as well as overlapping axonal and cellular guidance defects in specific neuron classes. We have linked individual HS modifications to two specific guidance systems, the sax-3/Robo and kal-1/Anosmin-1 systems, whose activity is dependent on different HS modifications in different cellular contexts. Our results demonstrate that the molecular diversity in HS encodes information that is crucial for different aspects of neuronal development.

Amino Acid Sequence↗
PubMed2004

A conserved postsynaptic transmembrane protein affecting neuromuscular signaling in Caenorhabditis elegans.

For a motor unit to function, neurons and muscle cells need to adopt their correct cell fate, form appropriate cellular contacts, and assemble a specific repertoire of signaling proteins into presynaptic and postsynaptic structures. In the nematode Caenorhabditis elegans, a disruption of any of these steps causes uncoordinated locomotory behavior (unc phenotype). We report here the positional cloning of a new unc gene, unc-122, which we show by mosaic analysis and tissue-specific rescue experiments to act in muscle to affect locomotory behavior. unc-122 codes for a phylogenetically conserved type II transmembrane protein with collagen repeats and a cysteine-rich olfactomedin domain. Together with uncharacterized proteins in C. elegans, Drosophila, and vertebrates, UNC-122 defines a novel family of proteins that we term "Colmedins." UNC-122 protein is expressed exclusively in muscle and coelomocytes and localizes to the postsynaptic surface of GABAergic and cholinergic neuromuscular junctions (NMJs). Presynaptic and postsynaptic structures are present and properly aligned in unc-122 mutant animals, yet the animals display neurotransmission defects characterized by an altered sensitivity toward drugs that interfere with cholinergic signaling. Moreover, unc-122 mutant animals display anatomical defects in motor axons that are likely a secondary consequence of neurotransmission defects. Both the neuroanatomical and locomotory defects worsen progressively during the life of an animal, consistent with a role of unc-122 in acute signaling at the NMJ. On the basis of motifs in the UNC-122 protein sequence that are characteristic of extracellular matrix proteins, we propose that UNC-122 is involved in maintaining a structural microenvironment that allows efficient neuromuscular signaling.

Animals↗
PubMed2004

Genomic cis-regulatory architecture and trans-acting regulators of a single interneuron-specific gene battery in C. elegans.

Gene batteries are sets of coregulated genes with common cis-regulatory elements that define the differentiated state of a cell. The nature of gene batteries for individual neuronal cellular subtypes and their linked cis-regulatory elements is poorly defined. Through molecular dissection of the highly modular cis-regulatory architecture of individual neuronally expressed genes, we have defined a conserved 16 bp cis-regulatory motif that drives gene expression in a single interneuron subtype, termed AIY, in the nematode Caenorhabditis elegans. This motif is bound and activated by the Paired- and LIM-type homeodomain proteins CEH-10 and TTX-3. Using genome-wide phylogenetic footprinting, we delineated the location, distribution, and evolution of AIY-specific cis-regulatory elements throughout the genome and thereby defined a large battery of AIY-expressed genes, all of which represent direct Paired/LIM homeodomain target genes. The identity of these homeodomain targets provides novel insights into the biology of the AIY interneuron.

Amino Acid Motifs↗
PubMed2004

Common logic of transcription factor and microRNA action.

Over the past few years, microRNAs (miRNAs) have emerged as abundant regulators of gene expression. Like many transcription factors (TFs), miRNAs are important determinants of cellular fate specification. Here I provide a conceptual framework for miRNA action in the context of creating cellular diversity in a developing organism, and emphasize the conceptual similarity of TF- and miRNA-mediated control of gene expression. Both TFs and miRNAs are trans-acting factors that exert their activity through composite cis-regulatory elements that are 'hard-wired' into DNA or RNA. TFs and miRNAs act in a largely combinatorial manner - that is, many different TFs or miRNAs control one gene - and they act cooperatively on their targets - that is, there are several cis-regulatory elements for a single TF or miRNA species in a target gene. Just as the set of TFs in a given cell type has been proposed to constitute a 'code' that specifies cellular differentiation, so 'miRNA codes' are likely to have conceptually similar roles in the specification of cell types.

Animals↗
PubMed2004

A genetic screen for neurite outgrowth mutants in Caenorhabditis elegans reveals a new function for the F-box ubiquitin ligase component LIN-23.

Axon pathfinding and target recognition are highly dynamic and tightly regulated cellular processes. One of the mechanisms involved in regulating protein activity levels during axonal and synaptic development is protein ubiquitination. We describe here the isolation of several Caenorhabditis elegans mutants, termed eno (ectopic/erratic neurite outgrowth) mutants, that display defects in axon outgrowth of specific neuron classes. One retrieved mutant is characterized by abnormal termination of axon outgrowth in a subset of several distinct neuron classes, including ventral nerve cord motor neurons, head motor neurons, and mechanosensory neurons. This mutant is allelic to lin-23, which codes for an F-box-containing component of an SCF E3 ubiquitin ligase complex that was previously shown to negatively regulate postembryonic cell divisions. We demonstrate that LIN-23 is a broadly expressed cytoplasmically localized protein that is required autonomously in neurons to affect axon outgrowth. Our newly isolated allele of lin-23, a point mutation in the C-terminal tail of the protein, displays axonal outgrowth defects similar to those observed in null alleles of this gene, but does not display defects in cell cycle regulation. We have thus defined separable activities of LIN-23 in two distinct processes, cell cycle control and axon patterning. We propose that LIN-23 targets distinct substrates for ubiquitination within each process.

Alleles↗
PubMed2003

A C. elegans CLIC-like protein required for intracellular tube formation and maintenance.

The Caenorhabditis elegans excretory canal is composed of a single elongated and branched cell that is tunneled by an inner lumen of apical character. Loss of the exc-4 gene causes a cystic enlargement of this intracellular tube. exc-4 encodes a member of the chloride intracellular channel (CLIC) family of proteins. EXC-4 protein localizes to various tubular membranes in distinct cell types, including the lumenal membrane of the excretory tubes. A conserved 55-amino acid domain enables EXC-4 translocation from the cytosol to the lumenal membrane. The tubular architecture of this membrane requires EXC-4 for both its formation and maintenance.

Amino Acid Sequence↗
PubMed2003

A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.

How left/right functional asymmetry is layered on top of an anatomically symmetrical nervous system is poorly understood. In the nematode Caenorhabditis elegans, two morphologically bilateral taste receptor neurons, ASE left (ASEL) and ASE right (ASER), display a left/right asymmetrical expression pattern of putative chemoreceptor genes that correlates with a diversification of chemosensory specificities. Here we show that a previously undefined microRNA termed lsy-6 controls this neuronal left/right asymmetry of chemosensory receptor expression. lsy-6 mutants that we retrieved from a genetic screen for defects in neuronal left/right asymmetry display a loss of the ASEL-specific chemoreceptor expression profile with a concomitant gain of the ASER-specific profile. A lsy-6 reporter gene construct is expressed in less than ten neurons including ASEL, but not ASER. lsy-6 exerts its effects on ASEL through repression of cog-1, an Nkx-type homeobox gene, which contains a lsy-6 complementary site in its 3' untranslated region and that has been shown to control ASE-specific chemoreceptor expression profiles. lsy-6 is the first microRNA to our knowledge with a role in neuronal patterning, providing new insights into left/right axis formation.

3' Untranslated Regions↗
PubMed2003

LIM homeobox gene-dependent expression of biogenic amine receptors in restricted regions of the C. elegans nervous system.

Biogenic amines regulate a variety of behaviors. Their functions are predominantly mediated through G-protein-coupled 7-transmembrane domain receptors (GPCR), 16 of which are predicted to exist in the genome sequence of the nematode Caenorhabditis elegans. We describe here the expression pattern of several of these aminergic receptors, including two serotonin receptors (ser-1 and ser-4), one tyramine receptor (ser-2), and two dopamine receptors (dop-1 and dop-2). Moreover, we describe distinct but partially overlapping expression patterns of different splice forms of the ser-2 tyramine receptor locus. We find that each of the aminergic receptor genes is expressed in restricted regions of the nervous system and that many of them reveal significant overlap with the expression of regulatory factors of the LIM homeobox (Lhx) gene family. We demonstrate that the expression of several of the biogenic amine receptors is abrogated in specific cell types in Lhx gene mutants, thus establishing a role for these Lhx genes in regulating aspects of neurotransmission. We extend these findings with other cell fate markers and show that the lim-4 Lhx gene is required for several but not all aspects of RID motor neuron differentiation and that the lim-6 Lhx gene is required for specific aspects of RIS interneuron differentiation. We also use aminergic receptor gfp reporter fusions as tools to visualize the anatomy of specific neurons in Lhx mutant backgrounds and find that the development of the elaborate dendritic branching pattern of the PVD harsh touch sensory neuron requires the mec-3 Lhx gene. Lastly, we analyze a mutant allele of the ser-2 tyramine receptor, a target of the ttx-3 Lhx gene in the AIY interneuron class. ser-2 mutants display none of the defects previously shown to be associated with loss of AIY function.

Alleles↗
PubMed2003

A transcriptional regulatory cascade that controls left/right asymmetry in chemosensory neurons of C. elegans.

The molecular mechanisms of differential pattern formation along the left/right (L/R) axis in the nervous system are poorly understood. The nervous system of the nematode Caenorhabditis elegans displays several examples of L/R asymmetry, including the directional asymmetry displayed by the two ASE taste receptor neurons, ASE left (ASEL) and ASE right (ASER). Although bilaterally symmetric in regard to all known morphological criteria, these two neurons display distinct chemosensory capacities that correlate with the L/R asymmetric expression of three putative sensory receptor genes, gcy-5, expressed only in ASER, and gcy-6 and gcy-7, expressed only in ASEL. In order to understand the genetic basis of L/R asymmetry establishment, we screened for mutants in which patterns of asymmetric gcy gene expression are disrupted, and we identified a cascade of several symmetrically and asymmetrically expressed transcription factors that are sequentially required to restrict gcy gene expression to either the left or right ASE cell. These factors include the zinc finger transcription factor che-1; the homeobox genes cog-1, ceh-36, and lim-6; and the transcriptional cofactors unc-37/Groucho and lin-49. Specific features of this regulatory hierarchy are sequentially acting repressive interactions and the finely balanced activity of antagonizing positive and negative regulatory factors. A key trigger for asymmetry is the L/R differential expression of the Nkx6-type COG-1 homeodomain protein. Our studies have thus identified transcriptional mediators of a putative L/R-asymmetric signaling event and suggest that vertebrate homologs of these proteins may have similar functions in regulating vertebrate brain asymmetries.

Animals↗
PubMed2003

Two neuronal, nuclear-localized RNA binding proteins involved in synaptic transmission.

While there is evidence that distinct protein isoforms resulting from alternative pre-mRNA splicing play critical roles in neuronal development and function, little is known about molecules regulating alternative splicing in the nervous system. Using Caenorhabditis elegans as a model for studying neuron/target communication, we report that unc-75 mutant animals display neuroanatomical and behavioral defects indicative of a role in modulating GABAergic and cholinergic neurotransmission but not neuronal development. We show that unc-75 encodes an RRM domain-containing RNA binding protein that is exclusively expressed in the nervous system and neurosecretory gland cells. UNC-75 protein, as well as a subset of related C. elegans RRM proteins, localizes to dynamic nuclear speckles; this localization pattern supports a role for the protein in pre-mRNA splicing. We found that human orthologs of UNC-75, whose splicing activity has recently been documented in vitro, are expressed nearly exclusively in brain and when expressed in C. elegans, rescue unc-75 mutant phenotypes and localize to subnuclear puncta. Furthermore, we report that the subnuclear-localized EXC-7 protein, the C. elegans ortholog of the neuron-restricted Drosophila ELAV splicing factor, acts in parallel to UNC-75 to also affect cholinergic synaptic transmission. In conclusion, we identified a new neuronal, putative pre-mRNA splicing factor, UNC-75, and show that UNC-75, as well as the C. elegans homolog of ELAV, is required for the fine tuning of synaptic transmission. These findings thus provide a novel molecular link between pre-mRNA splicing and presynaptic function.

Animals↗
PubMed2003

New insights into the diversity and function of neuronal immunoglobulin superfamily molecules.

Immunoglobulin superfamily (IgSF) proteins are implicated in diverse steps of brain development, including neuronal migration, axon pathfinding, target recognition and synapse formation, as well as in the maintenance and function of neuronal networks in the adult. We provide here a review of recent findings on the diversity and the role of transmembrane and secreted members of IgSF proteins in the nervous system. We illustrate that the complexity of IgSF protein function results from various different levels of regulation including regulation of gene expression, protein localization, and protein interactions.

Alternative Splicing↗
PubMed2003

Behavioral plasticity in C. elegans: paradigms, circuits, genes.

Life in the soil is an intellectual and practical challenge that the nematode Caenorhabditis elegans masters by utilizing 302 neurons. The nervous system assembled by these 302 neurons is capable of executing a variety of behaviors, some of respectable complexity. The simplicity of the nervous system, its thoroughly characterized structure, several sets of well-defined behaviors, and its genetic amenability combined with its isogenic background make C. elegans an attractive model organism to study the genetics of behavior. This review describes several behavioral plasticity paradigms in C. elegans and their underlying neuronal circuits and then goes on to review the forward genetic analysis that has been undertaken to identify genes involved in the execution of these behaviors. Lastly, the review outlines how reverse genetics and genomic approaches can guide the analysis of the role of genes in behavior and why and how they will complement the forward genetic analysis of behavior.

Adaptation, Physiological↗
PubMed2003

Functional mapping of neurons that control locomotory behavior in Caenorhabditis elegans.

One approach to understanding behavior is to define the cellular components of neuronal circuits that control behavior. In the nematode Caenorhabditis elegans, neuronal circuits have been delineated based on patterns of synaptic connectivity derived from ultrastructural analysis. Individual cellular components of these anatomically defined circuits have previously been characterized on the sensory and motor neuron levels. In contrast, interneuron function has only been addressed to a limited extent. We describe here several classes of interneurons (AIY, AIZ, and RIB) that modulate locomotory behavior in C. elegans. Using mutant analysis as well as microsurgical mapping techniques, we found that the AIY neuron class serves to tonically modulate reversal frequency of animals in various sensory environments via the repression of the activity of a bistable switch composed of defined command interneurons. Furthermore, we show that the presentation of defined sensory modalities induces specific alterations in reversal behavior and that the AIY interneuron class mediates this alteration in locomotory behavior. We also found that the AIZ and RIB interneuron classes process odorsensory information in parallel to the AIY interneuron class. AIY, AIZ, and RIB are the first interneurons directly implicated in chemosensory signaling. Our neuronal mapping studies provide the framework for further genetic and functional dissections of neuronal circuits in C. elegans.

Animals↗
PubMed2003

Development and maintenance of neuronal architecture at the ventral midline of C. elegans.

Work in flies, nematodes and vertebrates has shown that genes involved in axon patterning at the ventral midline are functionally conserved across phylogeny. Recent studies in Caenorhabditis elegans have implicated several new extracellular molecules, such as nidogen and heparan sulfate proteoglycans, in axonal tract formation at the midline. Furthermore, a conceptually new mechanism that regulates the maintenance of axon positioning at the midline has been described in C. elegans.

Animals↗