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      • Unconventional function of an Achaete-Scute homolog as a terminal selector of nociceptive neuron identity

        Masoudi, Neda,Tavazoie, Saeed,Glenwinkel, Lori,Ryu, Leesun,Kim, Kyuhyung,Hobert, Oliver Public Library of Science 2018 PLoS biology Vol.16 No.4

        <▼1><P>Proneural genes are among the most early-acting genes in nervous system development, instructing blast cells to commit to a neuronal fate. <I>Drosophila</I> Atonal and Achaete-Scute complex (AS-C) genes, as well as their vertebrate orthologs, are basic helix-loop-helix (bHLH) transcription factors with such proneural activity. We show here that a <I>C</I>. <I>elegans</I> AS-C homolog, <I>hlh-4</I>, functions in a fundamentally different manner. In the embryonic, larval, and adult nervous systems, <I>hlh-4</I> is expressed exclusively in a single nociceptive neuron class, ADL, and its expression in ADL is maintained via transcriptional autoregulation throughout the life of the animal. However, in <I>hlh-4</I> null mutants, the ADL neuron is generated and still appears neuronal in overall morphology and expression of panneuronal and pansensory features. Rather than acting as a proneural gene, we find that <I>hlh-4</I> is required for the ADL neuron to function properly, to adopt its correct morphology, to express its unusually large repertoire of olfactory receptor–encoding genes, and to express other known features of terminal ADL identity, including neurotransmitter phenotype, neuropeptides, ion channels, and electrical synapse proteins. <I>hlh-4</I> is sufficient to induce ADL identity features upon ectopic expression in other neuron types. The expression of ADL terminal identity features is directly controlled by HLH-4 via a phylogenetically conserved E-box motif, which, through bioinformatic analysis, we find to constitute a predictive feature of ADL-expressed terminal identity markers. The lineage that produces the ADL neuron was previously shown to require the conventional, transient proneural activity of another AS-C homolog, <I>hlh-14</I>, demonstrating sequential activities of distinct AS-C-type bHLH genes in neuronal specification. Taken together, we have defined here an unconventional function of an AS-C-type bHLH gene as a terminal selector of neuronal identity and we speculate that such function could be reflective of an ancestral function of an “ur-” bHLH gene.</P></▼1><▼2><P><B>Author summary</B></P><P>Across the animal kingdom, transcription factors of the basic helix-loop-helix (bHLH) family act during embryonic nervous system patterning as proneural genes to promote neuroblast identity. We describe here a distinct function for a specific member of this family, <I>hlh-4</I>, in the nematode <I>Caenorhabditis elegans</I>. <I>hlh-4</I> is exclusively expressed in a nociceptive neuron class and is not required for this neuron class to be generated but is rather required for the execution of its terminal differentiation program. <I>hlh-4</I> directly controls the expression of scores of terminal identity features of this neuron class, including its large battery of chemoreceptor-encoding genes. We propose that a role of bHLH genes in controlling terminal differentiation may be the ancestral function of members of this gene family.</P></▼2>

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