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Vidal, B.

Publications and source records attributed to Vidal, B..

13 recordsLinked to original sources
bioRxiv2026

Regulatory architecture controlling terminal differentiation of an interoceptive paraneuron in C. elegans

Interoceptive paraneurons are neuron-like cells located within internal epithelial cell surfaces that sense internal stimuli to evoke specific behavioral or physiological responses. The elucidation of terminal differentiation programs of paraneurons is expected to provide insights into how epithelial cells acquire neuron-like feature during development and possibly also over evolutionary time. We define here transcriptional programs that control the terminal differentiation of an interoceptive paraneuron class in the nematode C. elegans, called uv1. The uv1 cells sense mechanosensory inputs in the uterus and signal via the HSN neurons to modulate egg-laying behavior. We show that like in canonical neurons, the neuron-like secretory features of uv1 are controlled by a combination of CUT homeobox genes, while the combinatorial terminal gene battery that defines the unique functional features of uv1 is jointly controlled by a combination of at least three transcription factors, a LIM homeodomain (LIN-11), a SoxD (EGL-13) and a Pax family (EGL-38) protein. These factors act in a terminal selector-type manner to jointly co-regulate the many distinct uv1-paraneuron specific molecular features, such as sensory receptors, neuromodulatory receptors and neuropeptides, as well as uv1s tyraminergic identity. Our findings demonstrate notable similarities in the dichotomous architecture of gene regulatory programs of neurons and paraneurons.

developmental biology↗
bioRxiv2026

A conserved C. elegans zinc finger-homeodomain protein, ZFH-2, continuously required for structural integrity and function of alimentary tract and gonad

An unusually large transcription factor arose at the base of bilaterian evolution through domain shuffling that recombined many copies of two distinct DNA binding domains, C2H2-type zinc fingers and homeodomains. The function of this deeply conserved type of protein remains poorly characterized. We describe here the complete and complex expression pattern of its sole C. elegans representative, ZFH-2, throughout development and adulthood. We show that animals lacking this protein display defects in proper alimentary tract formation and starve to death in the first larval stage with an apparent inability to ingest food. Conditional removal of ZFH-2 at post-developmental stages reveals a continuous function of this protein in enabling food ingestion and demonstrates additional essential functions for the formation of other, postembryonically generated tubular structures. Even though ZFH-2 is broadly expressed throughout the nervous system, we detected no obvious defects in neuronal development or function in zfh-2 null mutants. Genome-engineered alleles indicate that while a large part of the protein is dispensable, at least a subset of the homeodomains are critical determinants for the essential functions of this protein.

developmental biology↗
bioRxiv2025

Minute- and second-scale hippocampal network dysfunctions in the 3xTgAD mouse model of Alzheimer's disease are prevented by TSPO knockout

The 18kDa translocator protein (TSPO) is widely recognized as a biomarker of neuroinflammation, but recent evidence suggests that it may also play a direct role in the pathophysiology of neurological conditions with an inflammatory component such as Alzheimers disease (AD). In this study, we leveraged functional ultrasound imaging (fUSi) to assess how TSPO knockout influences brain activity and connectivity in the 3xTgAD mouse model of AD. Resting-state scans were performed in 16-month-old male and female mice across four genotypes: WT, TSPO-/-, 3xTgAD or 3xTgAD.TSPO-/-. Using a data-driven approach, we identified key functional networks, including a bilateral hippocampal-amygdala limbic network. Dual regression analysis revealed increased engagement of the ventral hippocampus within the limbic network and elevated hemodynamic variance in 3xTgAD mice compared to WT. Moreover, co-activation patterns (CAPs) analysis showed abnormal activation/deactivation cycles involving the dorsal hippocampus, both of which were prevented by TSPO knockout without affecting amyloid or tau burden. Our findings highlight a functional role for TSPO in shaping network dynamics and suggest that its deletion can mitigate brain dysfunction in AD models.

neuroscience↗
bioRxiv2025

Integrating bulk and single cell RNA-seq refines transcriptomic profiles of individual C. elegans neurons

Neuron-specific morphology and function are fundamentally tied to differences in gene expression across the nervous system. We previously generated a single cell RNA-seq (scRNA-Seq) dataset for every anatomical neuron class in the C. elegans hermaphrodite. Here we present a complementary set of bulk RNA-seq samples for 52 of the 118 canonical neuron classes in C. elegans. We show that the bulk RNA-seq dataset captures both lowly expressed and noncoding RNAs that are not detected in the scRNA-Seq profile, but also includes false positives due to contamination by other cell types. We present an analytical strategy that integrates the two datasets, preserving both the specificity of scRNA-Seq data and the sensitivity of bulk RNA-Seq. We show that this integrated dataset enhances the sensitivity and accuracy of transcript detection and differential gene analysis. In addition, we show that the bulk RNA-Seq data set detects differentially expressed non-coding RNAs across neuron types, including multiple families of non-polyadenylated transcripts. We propose that our approach provides a new strategy for interrogating gene expression by bridging the gap between bulk and single cell methodologies for transcriptomic studies. We suggest that these datasets advance the goal of delineating the mechanisms that define morphology and connectivity in the nervous system.

genomics↗
bioRxiv2024

Functional analysis of conserved C. elegans bHLH family members uncovers lifespan control by a peptidergic hub neuron

Throughout the animal kingdom, several members of the basic helix-loop-helix (bHLH) family act as proneural genes during early steps of nervous system development. Roles of bHLH genes in specifying terminal differentiation of postmitotic neurons have been less extensively studied. We analyze here the function of five C. elegans bHLH genes, falling into three phylogenetically conserved subfamilies, which are continuously expressed in a very small number of postmitotic neurons in the central nervous system. We show (a) that two orthologs of the vertebrate bHLHb4/b5 genes, called hlh-17 and hlh-32, function redundantly to specify the identity of a single head interneuron (AUA), as well as an individual motor neuron (VB2), (b) that the PTF1a ortholog hlh-13 acts as a terminal selector to control terminal differentiation and function of the sole octopaminergic neuron class in C. elegans, RIC, and (c) that the NHLH1/2 ortholog hlh-15 controls terminal differentiation and function of the peptidergic AVK head interneuron class, a known neuropeptidergic signaling hub in the animal. Strikingly, through null mutant analysis and cell-specific rescue experiments, we find that loss of hlh-15/NHLH in the peptidergic AVK neurons and the resulting abrogation of neuropeptide secretion causes a substantially expanded lifespan of the animal, revealing an unanticipated impact of a central, peptidergic hub neuron in regulating lifespan, which we propose to be akin to hypothalamic control of lifespan in vertebrates. Taken together, our functional analysis reveals themes of bHLH gene function during terminal differentiation that are complementary to the earlier lineage specification roles of other bHLH family members. However, such late functions are much more sparsely employed by members of the bHLH transcription factor family, compared to the function of the much more broadly employed homeodomain transcription factor family.

neuroscience↗
bioRxiv2023

A neurotransmitter atlas of the nervous system of C.elegans males and hermaphrodites

Mapping neurotransmitter identities 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. In the C. elegans nervous system, neurotransmitter identities have been largely assigned by 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 relevant cis-regulatory information and therefore may not provide an accurate picture of neurotransmitter usage. We analyzed the expression patterns of 16 CRISPR/Cas9-engineered knock-in reporter strains for all main types of neurotransmitters in C. elegans (glutamate, acetylcholine, GABA, serotonin, dopamine, tyramine, and octopamine) in both the hermaphrodite and the male. Our analysis reveals novel sites of expression of these neurotransmitter systems within both neurons and glia, as well as non-neural cells. The resulting expression atlas defines neurons that may be exclusively neuropeptidergic, substantially expands the repertoire of neurons capable of co-transmitting multiple neurotransmitters, and identifies novel neurons that uptake monoaminergic neurotransmitters. Furthermore, we also observed unusual co-expression patterns of monoaminergic synthesis pathway genes, suggesting the existence of novel monoaminergic transmitters. Our analysis results in what constitutes the most extensive whole-animal-wide map of neurotransmitter usage to date, paving the way for a better understanding of neuronal communication and neuronal identity specification in C. elegans.

neuroscience↗
bioRxiv2022

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

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 20 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 20 neuron classes had no homeobox gene function ascribed to them before, while in the other 10 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, 111 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.

neuroscience↗
bioRxiv2022

Integrating bulk and single cell RNA-seq refines transcriptomic profiles of specific C. elegans neurons.

Neuron-specific morphology and function are fundamentally tied to differences in gene expression across the nervous system. We previously generated a single cell RNA-seq (scRNA-Seq) dataset for every anatomical neuron class in the C. elegans hermaphrodite. Here we present a complementary set of bulk RNA-seq samples for 52 of the 118 canonical neuron classes in C. elegans. We show that the bulk RNA-seq dataset captures both lowly expressed and noncoding RNAs that are not detected in the scRNA-Seq profile, but also includes false positives due to contamination by other cell types. We present an analytical strategy that integrates the two datasets, preserving both the specificity of scRNA-Seq data and the sensitivity of bulk RNA-Seq. We show that this integrated dataset enhances the sensitivity and accuracy of transcript detection and differential gene analysis. In addition, we show that the bulk RNA-Seq data set detects differentially expressed non-coding RNAs across neuron types, including multiple families of non-polyadenylated transcripts. We propose that our approach provides a new strategy for interrogating gene expression by bridging the gap between bulk and single cell methodologies for transcriptomic studies. We suggest that these datasets advance the goal of delineating the mechanisms that define morphology and connectivity in the nervous system.

genetics↗
bioRxiv2021

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

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.

neuroscience↗
bioRxiv2021

Targeting activated macrophages intracellular milieu to augment anti-inflammatory drug potency

We present pH-responsive phosphorylcholine polymersomes ability to target activated macrophages via scavenger receptors, enter them via endocytosis, and escape from early endosomes enabling the intra-cellular drug delivery. Using an arthritis experimental model and the gold standard disease modifying anti-rheumatic drug, methotrexate, we prove that polymersomes augments therapeutic efficacy, while minimizing the off-target effect. First, we demonstrate the selective accumulation of polymersomes within the inflamed synovial tissues and cells, including macrophages. Second, we show the beneficial therapeutic effect of methotrexate loaded polymersomes in preventing both joint inflammation and further damage. Hence, we prove the therapeutic potential of polymersomes in enhancing the complete prevention of arthritis progression, which makes it a promising nanotherapy for arthritis treatment as well as other inflammatory disorders. TeaserWe show that the effective targeting and delivery of drugs to the main inflammation actors, the macrophages, enhances arthritis therapy.

immunology↗
bioRxiv2020

Molecular topography of an entire nervous system

Nervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of the C. elegans nervous system that matches 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 unique codes of [~]23 neuropeptide-encoding genes and [~]36 neuropeptide receptors thus pointing to an expansive "wireless" signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at 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.

neuroscience↗
bioRxiv2019

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

A 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.

neuroscience↗
bioRxiv2017

An atlas of Caenorhabditis elegans chemoreceptor expression

One goal of modern day neuroscience is the establishment of molecular maps that assign unique features to individual neuron types. Such maps provide important starting points for neuron classification, for functional analysis and for developmental studies aimed at defining the molecular mechanisms of neuron identity acquisition and neuron identity diversification. In this resource paper, we describe a nervous system-wide map of the potential expression sites of 244 members of the largest gene family in the C. elegans genome, rhodopsin-like (class A) GPCR chemoreceptors, using classic gfp reporter gene technology. We cover representatives of all sequence families of chemoreceptors GPCRs, some of which were previously entirely uncharacterized. Most reporters are expressed in a very restricted number of cells, often just in single cells. We assign GPCR reporter expression to all but two of the 37 sensory neuron classes of the sex-shared, core nervous system. Some sensory neurons express a very small number of receptors, while others, particularly nociceptive neurons, co-express several dozen GPCR reporter genes. GPCR reporters are also expressed in a wide range of inter- and motorneurons, as well as nonneuronal cells, suggesting that GPCRs may constitute receptors not just for environmental signals, but also for internal cues. We observe only one notable, frequent association of coexpression patterns, namely in one nociceptive amphid (ASH) and two nociceptive phasmid sensory neurons (PHA, PHB). We identified GPCRs with sexually dimorphic expression and several GPCR reporters that are expressed in a left/right asymmetric manner. We identified a substantial degree of GPCR expression plasticity; particularly in the context of the environmentally-induced dauer diapause stage when one third of all tested GPCRs alter the cellular specificity of their expression within and outside the nervous system. Intriguingly, in a number of cases, the dauer-specific alterations of GPCR reporter expression in specific neuron classes are maintained during postdauer life and in some case new patterns are induced post-dauer, demonstrating that GPCR gene expression may serve as traits of life history. Taken together, our resource provides an entry point for functional studies and also offers a host of molecular markers for studying molecular patterning and plasticity of the nervous system.\n\nAUTHOR SUMMARYMaps of gene expression patterns in the nervous system provide an important resource for neuron classification, for functional analysis and for developmental studies that ask how different neurons acquire their unique identities. By analyzing transgenic gfp reporter strains, we describe here the expression pattern of 244 putative chemosensory receptor-encoding genes, which constitute the largest gene family in C.elegans. We show that, as expected, chemoreceptor expression is enriched in chemosensory neurons but it is also expressed in a wide range of interneurons, motorneurons, as well as non-neuronal cells, suggesting that putative chemosensory receptors may not just sense environmental signals but also internal cues. We find that each chemoreceptor is expressed in a few neuron types, often just one, but each neuron type can express a large number of chemoreceptors. Interestingly, we uncovered that chemoreceptor expression is remarkably plastic, particularly in the context of the environmentally-induced dauer diapause stage. Taken together, this molecular atlas of chemosensory receptors provides an entry point for functional studies and offers a host of markers for studying neuronal patterning and plasticity.

genetics↗