The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

Maicas, Miren; Jimeno-Martín, Ángela; Millán-Trejo, Andrea; Alkema, Mark J.; Flames, Nuria

doi:10.1371/journal.pbio.3001334

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…Since the reporter is targeted to the nucleus, this strategy circumvents shortcomings associated with interpreting antibody staining patterns or dealing with too densely packed cytosolic signals. For mod-5 , we analyzed an existing reporter allele ( Maicas et al 2021 ). For all our neuronal cell identification, we utilized the neuronal landmark strain NeuroPAL ( Tekieli et al 2021 ; Yemini et al 2021 ).…”

Section: Resultsmentioning

confidence: 99%

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A neurotransmitter atlas ofC. elegansmales and hermaphrodites

Wang,

Vidal,

Sural

et al. 2023

Preprint

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Assigning neurotransmitter identity to neurons is key to understanding information flow in a nervous system. It also provides valuable entry points for studying the development and plasticity of neuronal identity features. Neurotransmitter identities have been assigned to most neurons in theC. elegansnervous system through the expression pattern analysis of neurotransmitter pathway genes that encode neurotransmitter biosynthetic enzymes or transporters. However, many of these assignments have relied on multicopy reporter transgenes that may lack relevantcis-regulatory information and therefore may not provide an accurate picture of neurotransmitter usage. We analyzed the expression patterns of 13 CRISPR/Cas9-engineered reporter knock-in strains, which report on the deployment of all main types of neurotransmitters inC. elegans(glutamate, acetylcholine, GABA, serotonin, tyramine, and octopamine) throughout the entire nervous system of both the hermaphrodite and the male. Our analysis reveals novel sites of expression of these neurotransmitter systems within both neurons and glia and defines neurons that may be exclusively neuropeptidergic. Furthermore, we also identified unusual combinations of expression of monoaminergic synthesis pathway genes, suggesting the existence of novel monoaminergic transmitters. Our analysis results in what constitutes the most extensive nervous system-wide map of neurotransmitter usage to date, paving the way for a better understanding of neuronal communication inC. elegans.

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Section: Resultsmentioning

confidence: 99%

“…Using a promoter-based transgene and antibody staining, previous work had shown expression of the serotonin uptake transporter mod-5 in NSM, ADF, RIH, and AIM ( Jafari et al 2011 ; Maicas et al 2021 ). This matched the observations that RIH and AIM do not synthesize 5-HT (i.e.…”

Section: Resultsmentioning

confidence: 99%

A neurotransmitter atlas ofC. elegansmales and hermaphrodites

Wang,

Vidal,

Sural

et al. 2023

Preprint

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“…TFs with known roles in MA specification that were retrieved from the RNAi screen act at different developmental stages. For example, lag-1 CSL TF is expressed in the postmitotic ADF neuron but not earlier, acting as terminal selector ( Maicas et al 2021 ); lim-4 HD TF is expressed in the mother cell of ADF but not in the postmitotic neuron and regulates lag-1 expression ( Zheng et al 2005 ; Maicas et al 2021 ); and hlh-14 bHLH TF is expressed earlier in the lineage and its proneural activity is required to generate the variety of neurons arising from that lineage ( Poole et al 2011 ; Masoudi et al 2021 ). In addition, retrieved TFs known to affect PDE reporter expression also act at several steps of the specification/differentiation process: ceh-16 HD TF is required for correct asymmetric divisions of the PDE lineage (V5 progenitor) ( Huang et al 2009 ); lin-32 bHLH TF is a proneurogenic factor needed for the generation of PDE and its sister cell PVD neuron, similar to the role of hlh-14 in ADF ( Zhao and Emmons 1995 ); and ast-1 ETS TF affects terminal fate of PDE but not PVD neuron ( Flames and Hobert 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity

et al. 2022

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To systematically investigate the complexity of neuron-specification regulatory networks we performed an RNA interference (RNAi) screen against all 875 transcription factors (TFs) encoded in Caenorhabditis elegans genome and searched for defects in nine different neuron types of the monoaminergic (MA) superclass and two cholinergic motoneurons. We identified 91 TF candidates required for correct generation of these neuron types of which 28 were confirmed by mutant analysis. We found that correct reporter expression in each individual neuron type requires at least nine different TFs. Individual neuron types do not usually share TFs involved in their specification but share a common pattern of TFs belonging to the five most common TF families: Homeodomain (HD), basic Helix Loop Helix (bHLH), Zinc Finger (ZF), Basic Leucine Zipper Domain (bZIP) and Nuclear Hormone Receptors (NHR). HD TF members are over-represented, supporting a key role for this family in the establishment of neuronal identities. We found a similar TF family distribution for TF mutants with assigned phenotypes in any neuron type in C. elegans, Drosophila or mouse. In addition, we studied terminal differentiation complexity focusing on the dopaminergic terminal regulatory program. We found two HD TFs (UNC-62 and VAB-3) that work together with known dopaminergic terminal selectors (AST-1, CEH-43, CEH-20). Combined TF binding sites for these five TFs constitute a cis-regulatory signature enriched in the regulatory regions of dopaminergic effector genes. Our results provide new insights on neuron-type regulatory programs in C. elegans that could help better understand neuron specification and evolution of neuron types.

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“…Table S4: A regulatory map of transcription factors with a role in terminal neuron differentiation . The basis for this data is taken mainly from (Hobert, 2016a) and supplemented with data from this paper, as well as others, including (Berghoff et al, 2021; Gendrel et al, 2016; Jimeno-Martin et al, 2022; Lloret-Fernandez et al, 2018; Maicas et al, 2021; Reilly et al, 2020; Vidal et al, 2022; Zheng et al, 2022). Criteria to be included in this list is that the transcription factor is expressed throughout embryonic and postembryonic development of the respective neuron type, i.e.…”

Section: Supplementary Table Legendsmentioning

confidence: 99%

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

Reilly

Tekieli

Cros

et al. 2022

Preprint

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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 12 homeobox genes in 19 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 19 neuron classes had no homeobox gene function ascribed to them before, while in the other 9 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 analysis, 112 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 ancient feature of animal nervous systems.

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The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

Cited by 9 publications

References 58 publications

A neurotransmitter atlas ofC. elegansmales and hermaphrodites

A neurotransmitter atlas ofC. elegansmales and hermaphrodites

Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

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