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.

scholarly journals In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lori Glenwinkel ◽  
Seth R Taylor ◽  
Kasper Langebeck-Jensen ◽  
Laura Pereira ◽  
Molly B Reilly ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Single Cell ◽  
Expression Profiles ◽  
Neuronal Cell ◽  
In Silico Analysis ◽  
Specific Gene ◽  
Neuron Type ◽  
C Elegans ◽  
Neuronal Identity

The generation of the enormous diversity of neuronal cell types in a differentiating nervous system entails the activation of neuron type-specific gene batteries. To examine the regulatory logic that controls the expression of neuron type-specific gene batteries, we interrogate single cell expression profiles of all 118 neuron classes of the Caenorhabditis elegans nervous system for the presence of DNA binding motifs of 136 neuronally expressed C. elegans transcription factors. Using a phylogenetic footprinting pipeline, we identify cis-regulatory motif enrichments among neuron class-specific gene batteries and we identify cognate transcription factors for 117 of the 118 neuron classes. In addition to predicting novel regulators of neuronal identities, our nervous system-wide analysis at single cell resolution supports the hypothesis that many transcription factors directly co-regulate the cohort of effector genes that define a neuron type, thereby corroborating the concept of so-called terminal selectors of neuronal identity. Our analysis provides a blueprint for how individual components of an entire nervous system are genetically specified.

scholarly journals Ret loss-of-function decreases enteric neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

2021 ◽  
Author(s):  
Elizabeth Vincent ◽  
Sumantra Chatterjee ◽  
Gabrielle H Cannon ◽  
Dallas Auer ◽  
Holly Ross ◽  
...  
Keyword(s):  
Nervous System ◽  
Motor Neuron ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Expression Patterns ◽  
Critical Role ◽  
Nervous System Development ◽  
Developmental Trajectory ◽  
Loss Of Function ◽  
Gi Tract

The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Ret loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

scholarly journals Enteric nervous system modulation of luminal pH modifies the microbial environment to promote intestinal health

2021 ◽  
Author(s):  
M. Kristina Hamilton ◽  
Elena S. Wall ◽  
Karen Guillemin ◽  
Judith S. Eisen
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Intestinal Microbiota ◽  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Wild Type ◽  
Intestinal Health ◽  
Primary Function ◽  
Luminal Ph

AbstractThe enteric nervous system (ENS) controls many aspects of intestinal homeostasis, including parameters that shape the habitat of microbial residents. Previously we showed that zebrafish lacking an ENS, due to deficiency of the sox10 gene, develop intestinal inflammation and bacterial dysbiosis, with an expansion of proinflammatory Vibrio strains. To understand the primary defects resulting in dysbiosis in sox10 mutants, we investigated how the ENS shapes the intestinal environment in the absence of microbiota and associated inflammatory responses. We found that intestinal transit, intestinal permeability, and luminal pH regulation are all aberrant in sox10 mutants, independent of microbially induced inflammation. Treatment with the proton pump inhibitor, omeprazole, corrected the more acidic luminal pH of sox10 mutants to wild type levels. Omeprazole treatment also prevented overabundance of Vibrio and ameliorated inflammation in sox10 mutant intestines. Treatment with the carbonic anhydrase inhibitor, acetazolamide, caused wild type luminal pH to become more acidic, and increased both Vibrio abundance and intestinal inflammation. We conclude that a primary function of the ENS is to regulate luminal pH, which plays a critical role in shaping the resident microbial community and regulating intestinal inflammation.Author SummaryThe intestinal microbiota is an important determinant of health and disease and is shaped by the environment of the gut lumen. The nervous system of the intestine, the enteric nervous system (ENS), helps maintain many aspects of intestinal health including a healthy microbiota. We used zebrafish with a genetic mutation that impedes ENS formation to investigate how the ENS prevents pathogenic shifts in the microbiota. We found that mutants lacking an ENS have a lower luminal pH, higher load of pathogenic bacteria, and intestinal inflammation. We showed that correcting the low pH, using the commonly prescribed pharmacological agent omeprazole, restored the microbiota and prevented intestinal inflammation. Conversely, we found that lowering the luminal pH of wild type animals, using the drug acetazolamide, caused expansion of pathogenic bacteria and increased intestinal inflammation. From these experiments, we conclude that a primary function of the ENS is to maintain normal luminal pH, thereby constraining intestinal microbiota community composition and promoting intestinal health.

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.

Metabolism and inactivation of neurotransmitters in nematodes

Parasitology ◽  
1996 ◽  
Vol 113 (S1) ◽  
pp. S157-S173 ◽  
Author(s):  
R. E. Isaac ◽  
D. Macgregor ◽  
D. Coates
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Free Living ◽  
Nervous Systems ◽  
Target Proteins ◽  
C Elegans ◽  
Free Living Nematode ◽  
Increasing Knowledge ◽  
Insight Into

SUMMARYThe nematode nervous system employs many of the same neurotransmitters as are found in higher animals. The inactivation of neurotransmitters is absolutely essential for the correct functioning of the nervous system, In this article we discuss the various mechanisms used generally in animal nervous systems for synaptic inactivation of neurotransmitters and review the evidence for similar mechanisms operating in parasitic and free-living nematodes. The sequencing of the entireCaenorhabditis elegansgenome means that the sequence of nematode genes can be accessed from theC. elegansdatabase (ACeDB) and this wealth of information together with the increasing knowledge of the genetics of this free-living nematode will have great impact on all aspects of nematode neurobiology. The review will provide an insight into how this information may be exploited to identify and characterize target proteins for the development of novel anti-nematode drugs.

scholarly journals A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans

2013 ◽  
Vol 27 (12) ◽  
pp. 1391-1405 ◽  
Author(s):  
M. Doitsidou ◽  
N. Flames ◽  
I. Topalidou ◽  
N. Abe ◽  
T. Felton ◽  
...  
Keyword(s):  
Nervous System ◽  
Terminal Differentiation ◽  
C Elegans

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 Transcription factors from multiple families ensure enhancer selectivity and robust neuron terminal differentiation

2020 ◽  
Author(s):  
Angela Jimeno-Martín ◽  
Erick Sousa ◽  
Noemi Daroqui ◽  
Rebeca Brocal-Ruiz ◽  
Miren Maicas ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Rna Interference ◽  
Terminal Differentiation ◽  
Specific Gene ◽  
Neuron Type ◽  
C Elegans ◽  
Effector Genes ◽  
Genetic Robustness ◽  
Gene Regulatory ◽  
Dopaminergic Terminal

SUMMARYTo search for general principles underlying neuronal regulatory programs we built an RNA interference library against all transcription factors (TFs) encoded in C. elegans genome and systematically screened for specification defects in ten different neuron types of the monoaminergic (MA) superclass.We identified over 90 TFs involved in MA specification, with at least ten different TFs controlling differentiation of each individual neuron type. These TFs belong predominantly to five TF families (HD, bHLH, ZF, bZIP and NHR). Next, focusing on the complexity of terminal differentiation, we identified and functionally characterized the dopaminergic terminal regulatory program. We found that seven TFs from four different families act in a TF collective to provide genetic robustness and to impose a specific gene regulatory signature enriched in the regulatory regions of dopamine effector genes. Our results provide new insights on neuron-type regulatory programs that could help better understand specification and evolution of neuron types.

scholarly journals Timing mechanism of sexually dimorphic nervous system differentiation

2018 ◽  
Author(s):  
Laura Pereira ◽  
Florian Aeschimann ◽  
Chen Wang ◽  
Hannah Lawson ◽  
Esther Serrano-Saiz ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Sexual Maturation ◽  
Sexual Differentiation ◽  
Rna Binding ◽  
Receptor Expression ◽  
Sexually Dimorphic ◽  
Neuron Type ◽  
C Elegans ◽  
Male Specific

ABSTRACTIn all animals, sexual differentiation of somatic tissue is precisely timed, yet the molecular mechanisms that control the timing of sexual differentiation, particularly in the brain, are poorly understood. We have used sexually dimorphic molecular, anatomical and behavioral features of the C. elegans nervous system to decipher a regulatory pathway that controls the precise timing of sexual differentiation. We find that the sexually dimorphic differentiation of postmitotic neurons in the male nervous system is abrogated in animals that carry a mutation in the miRNA let-7 and prematurely executed in animals either lacking the let-7 inhibitor lin-28, or the direct let-7 target lin-41, an RNA-binding, posttranscriptional regulator. We show that an isoform of a phylogenetically conserved transcription factor, lin-29a, is a critical target of LIN-41 in controlling sexual maturation of sex-shared neurons. lin-29a is expressed in a male-specific manner in a subset of sex-shared neurons at the onset of sexual maturation. lin-29a acts cell-autonomously in these neurons to control the expression of sexually dimorphic neurotransmitter switches, sensory receptor expression, neurite anatomy and connectivity, and locomotor behavior. lin-29a is not only required but also sufficient to impose male-specific features at earlier stages of development and in the opposite sex. The temporal, sexual and spatial specificity of lin-29a expression is controlled intersectionally through the lin-28/let-7/lin-41 heterochronic pathway, sex chromosome configuration and neuron type-specific terminal selector transcription factors. Two Doublesex-like transcription factors represent additional neuron-type specific targets of LIN-41 and are regulated in a similar intersectional manner, indicating the existence of modular outputs downstream of the heterochronic pathway. In conclusion, we have provided insights into the molecular logic of the timing of sexual differentiation in the C. elegans nervous system. Remarkably, the lin28/let7 axis also controls the timing of sexual differentiation in mice and humans thereby hinting toward a striking universality of the control mechanisms of sexual differentiation.

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