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WIREs Dev Biol
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A map of terminal regulators of neuronal identity in Caenorhabditis elegans

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Our present day understanding of nervous system development is an amalgam of insights gained from studying different aspects and stages of nervous system development in a variety of invertebrate and vertebrate model systems, with each model system making its own distinctive set of contributions. One aspect of nervous system development that has been among the most extensively studied in the nematode Caenorhabditis elegans is the nature of the gene regulatory programs that specify hardwired, terminal cellular identities. I first summarize a number of maps (anatomical, functional, and molecular) that describe the terminal identity of individual neurons in the C. elegans nervous system. I then provide a comprehensive summary of regulatory factors that specify terminal identities in the nervous system, synthesizing these past studies into a regulatory map of cellular identities in the C. elegans nervous system. This map shows that for three quarters of all neurons in the C. elegans nervous system, regulatory factors that control terminal identity features are known. In‐depth studies of specific neuron types have revealed that regulatory factors rarely act alone, but rather act cooperatively in neuron‐type specific combinations. In most cases examined so far, distinct, biochemically unlinked terminal identity features are coregulated via cooperatively acting transcription factors, termed terminal selectors, but there are also cases in which distinct identity features are controlled in a piecemeal fashion by independent regulatory inputs. The regulatory map also illustrates that identity‐defining transcription factors are reemployed in distinct combinations in different neuron types. However, the same transcription factor can drive terminal differentiation in neurons that are unrelated by lineage, unrelated by function, connectivity and neurotransmitter deployment. Lastly, the regulatory map illustrates the preponderance of homeodomain transcription factors in the control of terminal identities, suggesting that these factors have ancient, phylogenetically conserved roles in controlling terminal neuronal differentiation in the nervous system. WIREs Dev Biol 2016, 5:474–498. doi: 10.1002/wdev.233 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Invertebrate Organogenesis > Worms Nervous System Development > Worms
Terminal selector regulons. (a) Schematic illustration of terminal identity features that are controlled by terminal selector‐type transcription factors. These identity features are continuously expressed throughout the life of a neuron. (b) Three examples of terminal selector regulons. All genes shown here were shown to be direct targets of the indicated terminal selectors. In addition to the genes shown here, scores of additional genes have been identified as being expressed in the respective neuron types and containing binding sites for the respective regulators, but these additional genes have not been validated for terminal selector‐dependence.
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Terminal regulators of motor neurons. Schematic worm with only motor neurons colored and tabular summary of terminal regulators of neuronal identity. See legend to Figure for an explanation of colors and numbers.
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Terminal regulators of interneurons. Schematic worm with only interneurons colored and tabular summary of terminal regulators of neuronal identity. See legend to Figure for an explanation of colors and numbers. * indicates our own unpublished data. ** lim‐6 and ceh‐14 regulate, in conjunction with the lin‐14 heterochronic gene, temporally controlled but not continuously expressed genes in PVT.
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Terminal regulators of sensory neurons. Schematic worm with only sensory neurons colored and tabular summary of terminal regulators of neuronal identity. Color code of neurons in the schematic refer to neurotransmitter identity as show in the tabular summary. ‘Terminal regulators’ refers to the key property of these transcription factors: they are expressed in mature neurons throughout their lifetime, likely a reflection of their continuous role in maintaining the differentiated, terminal state. Early or transiently acting regulators are not shown. Only extrapharyngeal neurons are shown. Black font: most/all tested markers affected (terminal selector). Blue font: only subsets of markers affected. (x/y) indicates x markers out of y markers tested show defective expression. Homeodomain transcription factors are underlined. * indicates that in the case of the touch neurons, expression profiling has identified at least 71 mec‐3‐dependent genes. unc‐86 is known to regulate mec‐3 expression and cooperate with mec‐3 to control touch neuron‐expressed genes. ** indicates that the blue labeled factors control only a small subset of left/right asymmetrically expressed chemoreceptors, but not bilateral identity of these neurons. *** indicates our own unpublished data. ‘Cilium’ indicates that the respective regulators also control cilium structure, as assessed by dye‐filling defects observed in the respective mutants.
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Lack of correlation of lineage with neurotransmitter identity or transcription factor expression. Each bar represents an individual cell. See text for references.
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Molecular maps of the C. elegans nervous system. (a) Examples of transgenic worms expressing gfp reporter transgenes. (Reprinted with permission from Ref . Copyright 2004) (b) Manually curated expression patterns of transgenes throughout the C. elegans nervous system, kindly extracted from www.wormbase.org by Daniela Raciti and Wen Chen and organized by Lori Glenwinkel. Note that these transgenes may not display the complete expression pattern of the respective gene, but they nevertheless serve as invaluable readouts of the regulatory state of a neuron. (c) Schematic map of neurotransmitter usage in the C. elegans head. (Reprinted with permission from Ref . Copyright 2015)
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An anatomical and lineage map of the C. elegans nervous system. (a) Illustrations of the entire nervous system and fascicles, kindly provided by Openworm.org. (b) Connectome. (Adapted from Ref .) (c) One example of a single neuron type, the glutamatergic RIA interneurons, labeled with gfp (Adapted from Ref .) and its synaptic connectivity. (Adapted from Ref .) (d) Lineage of cells generated in the embryo. Red lines indicate neurons.
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Regulation of pan‐neuronal identity. (Reprinted with permission from . Copyright 2015)
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Redeployment of regulators of terminal neuronal identity in distinct neuron types. Data are extracted from Figure . Coloring scheme indicates neurotransmitter identity: yellow = Glu, red = ACh, green = aminergic, black = unknown. Only transcription factors that operate in >1 class are shown
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