scholarly journals A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 1951-1969 ◽  
Author(s):  
Zeynep Altun-Gultekin ◽  
Yoshiki Andachi ◽  
Ephraim L. Tsalik ◽  
David Pilgrim ◽  
Yuji Kohara ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Homeodomain Proteins ◽  
Differentiation Markers ◽  
Regulatory Relationship ◽  
C Elegans ◽  
Regulatory Cascade ◽  
The Individual

The development of the nervous system requires the coordinated activity of a variety of regulatory factors that define the individual properties of specific neuronal subtypes. We report a regulatory cascade composed of three homeodomain proteins that act to define the properties of a specific interneuron class in the nematode C. elegans. We describe a set of differentiation markers characteristic for the AIY interneuron class and show that the ceh-10 paired-type and ttx-3 LIM-type homeobox genes function to regulate all known subtype-specific features of the AIY interneurons. In contrast, the acquisition of several pan-neuronal features is unaffected in ceh-10 and ttx-3 mutants, suggesting that the activity of these homeobox genes separates pan-neuronal from subtype-specific differentiation programs. The LIM homeobox gene ttx-3 appears to play a central role in regulation of AIY differentiation. Not only are all AIY subtype characteristics lost in ttx-3 mutants, but ectopic misexpression of ttx-3 is also sufficient to induce AIY-like features in a restricted set of neurons. One of the targets of ceh-10 and ttx-3 is a novel type of homeobox gene, ceh-23. We show that ceh-23 is not required for the initial adoption of AIY differentiation characteristics, but instead is required to maintain the expression of one defined AIY differentiation feature. Finally, we demonstrate that the regulatory relationship between ceh-10, ttx-3 and ceh-23 is only partially conserved in other neurons in the nervous system. Our findings illustrate the complexity of transcriptional regulation in the nervous system and provide an example for the intricate interdependence of transcription factor action.

The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 881-896 ◽  
Author(s):  
I. Valarche ◽  
J.P. Tissier-Seta ◽  
M.R. Hirsch ◽  
S. Martinez ◽  
C. Goridis ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Peripheral Nervous System ◽  
Transcriptional Activation ◽  
Promoter Activity ◽  
Regulatory Element ◽  
Homeodomain Protein ◽  
Sensory Ganglia ◽  
Homeodomain Proteins ◽  
Regulatory Cascade

Transcriptional regulation of the gene encoding the cell adhesion receptor NCAM (neural cell adhesion molecule), a putative effector molecule of a variety of morphogenetic events, is likely to involve important regulators of morphogenesis. Here we identify two mouse homeodomain proteins that bind to an upstream regulatory element in the Ncam promoter: Cux, related to Drosophila cut and human CDP, and Phox2, a novel protein with a homeodomain related to that of the Drosophila paired gene. In transient transfection experiments, Cux was found to be a strong inhibitor of Ncam promoter activity, and this inhibition could be relieved by simultaneously overexpressing Phox2. These results suggest that the Ncam gene might be a direct target of homeodomain proteins and provide a striking example of regulatory cross-talk between homeodomain proteins of different classes. Whereas the expression pattern of Cux/CDP includes many NCAM-negative sites, Phox2 expression was restricted to cells also expressing Ncam or their progenitors. The localisation data thus strongly reinforce the notion that Phox2 plays a role in transcriptional activation of Ncam in Phox2-positive cell types. In the peripheral nervous system, Phox2 was strongly expressed in all ganglia of the autonomic nervous system and more weakly in some cranial sensory ganglia, but not in the sensory ganglia of the trunk. Phox2 transcripts were detected in the primordia of sympathetic ganglia as soon as they form. Phox2 expression in the brain was confined to spatially restricted domains in the hindbrain, which correspond to the noradrenergic and adrenergic nuclei once they are identifiable. All Phox2-expressing components of the peripheral nervous system are at least transiently adrenergic or noradrenergic. In the developing brain, Phox2 was expressed at all known locations of (nor)adrenergic neurones and of their precursors. These results suggest that Phox2, in addition to regulating the NCAM gene, may be part of the regulatory cascade that controls the differentiation of neurons towards this neurotransmitter phenotype.

The Caenorhabditis elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons

Development ◽  
1999 ◽  
Vol 126 (7) ◽  
pp. 1547-1562 ◽  
Author(s):  
O. Hobert ◽  
K. Tessmar ◽  
G. Ruvkun
Keyword(s):  
Epithelial Cells ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Acid Decarboxylase ◽  
Neural Function ◽  
C Elegans ◽  
Gaba Synthesis ◽  
And Function ◽  
Rate Limiting ◽  
Enteric Muscle

We describe here the functional analysis of the C. elegans LIM homeobox gene lim-6, the ortholog of the mammalian Lmx-1a and b genes that regulate limb, CNS, kidney and eye development. lim-6 is expressed in a small number of sensory-, inter- and motorneurons, in epithelial cells of the uterus and in the excretory system. Loss of lim-6 function affects late events in the differentiation of two classes of GABAergic motorneurons which control rhythmic enteric muscle contraction. lim-6 is required to specify the correct axon morphology of these neurons and also regulates expression of glutamic acid decarboxylase, the rate limiting enzyme of GABA synthesis in these neurons. Moreover, lim-6 gene activity and GABA signaling regulate neuroendocrine outputs of the nervous system. In the chemosensory system lim-6 regulates the asymmetric expression of a probable chemosensory receptor. lim-6 is also required in epithelial cells for uterine morphogenesis. We compare the function of lim-6 to those of other LIM homeobox genes in C. elegans and suggest that LIM homeobox genes share the common theme of controlling terminal neural differentiation steps that when disrupted lead to specific neuroanatomical and neural function defects.

Regulation of ectodermal and excretory function by the C. elegans POU homeobox gene ceh-6

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 779-790 ◽  
Author(s):  
T.R. Burglin ◽  
G. Ruvkun
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Null Mutant ◽  
Reporter Construct ◽  
Excretory Function ◽  
C Elegans ◽  
Gfp Reporter ◽  
Excretory Cell

Caenorhabditis elegans has three POU homeobox genes, unc-86, ceh-6 and ceh-18. ceh-6 is the ortholog of vertebrate Brn1, Brn2, SCIP/Oct6 and Brn4 and fly Cf1a/drifter/ventral veinless. Comparison of C. elegans and C. briggsae CEH-6 shows that it is highly conserved. C. elegans has only three POU homeobox genes, while Drosophila has five that fall into four families. Immunofluorescent detection of the CEH-6 protein reveals that it is expressed in particular head and ventral cord neurons, as well as in rectal epithelial cells, and in the excretory cell, which is required for osmoregulation. A deletion of the ceh-6 locus causes 80% embryonic lethality. During morphogenesis, embryos extrude cells in the rectal region of the tail or rupture, indicative of a defect in the rectal epithelial cells that express ceh-6. Those embryos that hatch are sick and develop vacuoles, a phenotype similar to that caused by laser ablation of the excretory cell. A GFP reporter construct expressed in the excretory cell reveals inappropriate canal structures in the ceh-6 null mutant. Members of the POU-III family are expressed in tissues involved in osmoregulation and secretion in a number of species. We propose that one evolutionary conserved function of the POU-III transcription factor class could be the regulation of genes that mediate secretion/osmoregulation.

scholarly journals NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging in C. elegans

2019 ◽  
Author(s):  
Eviatar Yemini ◽  
Albert Lin ◽  
Amin Nejatbakhsh ◽  
Erdem Varol ◽  
Ruoxi Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Cell Fate ◽  
Activity Patterns ◽  
Expression Patterns ◽  
Yellow Emission ◽  
Metabotropic Receptors ◽  
Whole Brain ◽  
C Elegans

ABSTRACTComprehensively resolving single neurons and their cellular identities from whole-brain fluorescent images is a major challenge. We achieve this in C. elegans through the engineering and use of a multicolor transgene called NeuroPAL (a Neuronal Polychromatic Atlas of Landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that allows comprehensive determination of neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. Here we showcase three studies that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover novel changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding and novel neuronal asymmetries for these stimuli. We present a software package that enables semi-automated determination of all neuronal identities based on color and positional information. The NeuroPAL framework and software provide a means to design landmark atlases for other tissues and organisms. In conclusion, we expect NeuroPAL to serve as an invaluable tool for gene expression analysis, neuronal fate studies, and for mapping whole-brain activity patterns.

scholarly journals Visualizing the organization and differentiation of the male-specific nervous system of C. elegans

2021 ◽  
Author(s):  
Tessa Tekieli ◽  
Eviatar Yemini ◽  
Amin Nejatbakhsh ◽  
Erdem Varol ◽  
Robert W Fernandez ◽  
...  
Keyword(s):  
Nervous System ◽  
Just In Time ◽  
Differentiation Markers ◽  
C Elegans ◽  
Larval Stages ◽  
Fourth Larval Stage ◽  
Developmental Patterning ◽  
Male Specific ◽  
Cluster Gene ◽  
The Brain

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode C. elegans. While 294 neurons are shared between the two sexes, the nervous system of the male contains an additional 93 male-specific neurons, most of which have received very little attention so far. To make these neurons amenable for future study, we describe here how a multicolor, multipromoter reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male specific neurons. We used this tool to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes. We demonstrate the usage of NeuroPAL for cellular fate analysis by analyzing the effect of removal of developmental patterning genes, including a HOX cluster gene (egl-5), a miRNA (lin-4) and a proneural gene (lin-32/Ato), on neuronal identity acquisition within the male-specific nervous system. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage that is concomitant with male tale retraction. This wave of differentiation couples neuronal maturation programs with the appearance of sexual organs. We call this wave 'just-in-time' differentiation by its analogy to the mechanism of 'just-in-time' transcription of metabolic pathway genes.

scholarly journals Expression profiling of the mature C. elegans nervous system by single-cell RNA-Sequencing

2019 ◽  
Author(s):  
Seth R Taylor ◽  
Gabriel Santpere ◽  
Molly Reilly ◽  
Lori Glenwinkel ◽  
Abigail Poff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Single Cell ◽  
Web Application ◽  
Model Organism ◽  
Structural Motif ◽  
Individual Neuron ◽  
C Elegans ◽  
Link Type ◽  
The Individual

AbstractA single neuron and its synapses define the fundamental structural motif of the brain but the underlying gene expression programs that specify individual neuron types are poorly understood. To address this question in a model organism, we have produced a gene expression profile of >90% of the individual neuron classes in the C. elegans nervous system, an ensemble of neurons for which both the anatomy and connectivity are uniquely defined at single cell resolution. We generated single cell transcriptomes for 52,412 neurons that resolve as clusters corresponding to 109 of the canonical 118 neuron classes in the mature hermaphrodite nervous system. Detailed analysis revealed molecular signatures that further subdivide identified classes into specific neuronal subtypes. Notably, neuropeptide-related genes are often differentially expressed between subtypes of the given neuron class which points to distinct functional characteristics. All of these data are publicly available at our website (http://www.cengen.org) and can be interrogated at the web application SCeNGEA (https://cengen.shinyapps.io/SCeNGEA). We expect that this gene expression catalog will spur the goal of delineating the underlying mechanisms that define the developmental lineage, detailed anatomy, synaptic connectivity and function of each type of C. elegans neuron.

scholarly journals The conserved ASCL1/MASH-1 ortholog HLH-3 specifies sex-specific ventral cord motor neuron fate in C. elegans

2020 ◽  
Author(s):  
Lillian M. Perez ◽  
Aixa Alfonso
Keyword(s):  
Motor Neuron ◽  
Cell Fate ◽  
Motor Neurons ◽  
Bhlh Protein ◽  
Differentiation Markers ◽  
C Elegans ◽  
Ventral Cord ◽  
Neural Specification

ABSTRACTNeural specification can be regulated by one or many transcription factors. Here we identify a novel role for one conserved proneural factor, the bHLH protein HLH-3, implicated in the specification of sex-specific ventral cord motor neurons in C. elegans. In the process of characterizing the role of hlh-3 in neural specification, we document that differentiation of the ventral cord type C neurons, VCs, within their motor neuron class, is dynamic in time and space. Expression of VC class-specific and subclass-specific identity genes is distinct through development and dependent on where they are along the A-P axis (and their position in proximity to the vulva). Our characterization of the expression of VC class and VC subclass-specific differentiation markers in the absence of hlh-3 function reveals that VC fate specification, differentiation, and morphology requires hlh-3 function. Finally, we conclude that hlh-3 cell-autonomously specifies VC cell fate.

scholarly journals The Prop1-like homeobox gene unc-42 specifies the identity of synaptically connected neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Emily G Berghoff ◽  
Lori Glenwinkel ◽  
Abhishek Bhattacharya ◽  
HaoSheng Sun ◽  
Erdem Varol ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Homeobox Gene ◽  
Synaptic Connectivity ◽  
Axon Pathfinding ◽  
C Elegans ◽  
Neuronal Identity ◽  
Anatomical Analysis ◽  
Neuropeptide Receptors ◽  
Functional Circuitry

Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby potentially leaving overarching themes in gene function undiscovered. We show here that the Caenorhabditis elegans Prop1-like homeobox gene unc-42 is expressed in 15 distinct sensory, inter- and motor neuron classes throughout the entire C. elegans nervous system. Strikingly, all 15 neuron classes expressing unc-42 are synaptically interconnected, prompting us to investigate whether unc-42 controls the functional properties of this circuit and perhaps also the assembly of these neurons into functional circuitry. We found that unc-42 defines the routes of communication between these interconnected neurons by controlling the expression of neurotransmitter pathway genes, neurotransmitter receptors, neuropeptides, and neuropeptide receptors. Anatomical analysis of unc-42 mutant animals reveals defects in axon pathfinding and synaptic connectivity, paralleled by expression defects of molecules involved in axon pathfinding, cell-cell recognition, and synaptic connectivity. We conclude that unc-42 establishes functional circuitry by acting as a terminal selector of functionally connected neuron types. We identify a number of additional transcription factors that are also expressed in synaptically connected neurons and propose that terminal selectors may also function as ‘circuit organizer transcription factors’ to control the assembly of functional circuitry throughout the nervous system. We hypothesize that such organizational properties of transcription factors may be reflective of not only ontogenetic, but perhaps also phylogenetic trajectories of neuronal circuit establishment.

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

2003 ◽  
Vol 263 (1) ◽  
pp. 81-102 ◽  
Author(s):  
Ephraim L Tsalik ◽  
Timothy Niacaris ◽  
Adam S Wenick ◽  
Kelvin Pau ◽  
Leon Avery ◽  
...  
Keyword(s):  
Nervous System ◽  
Biogenic Amine ◽  
Homeobox Gene ◽  
C Elegans ◽  
Amine Receptors

scholarly journals The enteric nervous system of C. elegans is specified by the Sine Oculis-like homeobox gene ceh-34

2021 ◽  
Author(s):  
Berta Vidal ◽  
Burcu Gulez ◽  
Wen Xi Cao ◽  
Eduardo Leyva Diaz ◽  
Tessa Tekieli ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Critical Role ◽  
Terminal Differentiation ◽  
Homeobox Gene ◽  
Neuron Type ◽  
Nervous Systems ◽  
Sine Oculis ◽  
C Elegans ◽  
Circuit Assembly

Overarching themes in the terminal differentiation of the enteric nervous system, an autonomously acting unit of animal nervous systems, have so far eluded discovery. We describe here the overall regulatory logic of enteric nervous system differentiation of the nematode C. elegans that resides within the foregut (pharynx) of the worm. A Caenorhabditis elegans homolog of the Drosophila Sine Oculis homeobox gene, ceh-34, is expressed in all 14 classes of interconnected pharyngeal neurons from their birth throughout their life time, but in no other neuron type of the entire animal. Constitutive and temporally controlled ceh-34 removal shows that ceh-34 is required to initiate and maintain the neuron type-specific terminal differentiation program of all pharyngeal neuron classes, including their circuit assembly, without affecting panneuronal features. Through additional genetic loss of function analysis, we show that within each pharyngeal neuron class, ceh-34 cooperates with different homeodomain transcription factors to individuate distinct pharyngeal neuron classes. Our analysis underscores the critical role of homeobox genes in neuronal identity specification and links them to the control of neuronal circuit assembly of the enteric nervous system. Together with the pharyngeal nervous system simplicity as well as its specification by a Sine Oculis homolog, our findings invite speculations about the early evolution of nervous systems.

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