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1.
PLoS Genet ; 18(9): e1010372, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36178933

RESUMO

Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 14 homeobox genes in 24 distinct neuron classes that are mostly unrelated by location, function and lineage history. 12 of these 24 neuron classes had no homeobox gene function ascribed to them before, while in the other 12 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analyses, 113 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Emprego , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Elife ; 112022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35324425

RESUMO

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 Caenorhabditis elegans that resides within the foregut (pharynx) of the worm. A C. 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. 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.


Assuntos
Proteínas de Caenorhabditis elegans , Sistema Nervoso Entérico , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio , Fatores de Transcrição , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sistema Nervoso Entérico/embriologia , Sistema Nervoso Entérico/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Faringe , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Cell ; 184(16): 4329-4347.e23, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34237253

RESUMO

We have produced gene expression profiles of all 302 neurons of the C. elegans nervous system that match the single-cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses distinct codes of ∼23 neuropeptide genes and ∼36 neuropeptide receptors, delineating a complex and expansive "wireless" signaling network. To demonstrate the utility of this comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression and (2) reveal adhesion proteins with potential roles in process placement and synaptic specificity. Our expression data are available at https://cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity, and function throughout the C. elegans nervous system.


Assuntos
Caenorhabditis elegans/metabolismo , Sistema Nervoso/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Corantes Fluorescentes/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Larva/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Motivos de Nucleotídeos/genética , RNA-Seq , Sequências Reguladoras de Ácido Nucleico/genética , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica
4.
Elife ; 102021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34165430

RESUMO

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.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/fisiologia , Fatores de Transcrição/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Simulação por Computador , Sistema Nervoso/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo
5.
Nature ; 584(7822): 595-601, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32814896

RESUMO

It is not known at present whether neuronal cell-type diversity-defined by cell-type-specific anatomical, biophysical, functional and molecular signatures-can be reduced to relatively simple molecular descriptors of neuronal identity1. Here we show, through examination of the expression of all of the conserved homeodomain proteins encoded by the Caenorhabditis elegans genome2, that the complete set of 118 neuron classes of C. elegans can be described individually by unique combinations of the expression of homeodomain proteins, thereby providing-to our knowledge-the simplest currently known descriptor of neuronal diversity. Computational and genetic loss-of-function analyses corroborate the notion that homeodomain proteins not only provide unique descriptors of neuron type, but also have a critical role in specifying neuronal identity. We speculate that the pervasive use of homeobox genes in defining unique neuronal identities reflects the evolutionary history of neuronal cell-type specification.


Assuntos
Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Regulação da Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Neurônios/classificação , Neurônios/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Genoma/genética , Proteínas de Homeodomínio/genética , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neurônios/citologia
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