Biology subjects

Horvitz, H. R.

Publications and source records attributed to Horvitz, H. R..

9 recordsLinked to original sources

bioRxiv2026

The nonsense-mediated decay RNA-surveillance pathway facilitates the hypoxia response by C. elegans

Hypoxia (low O2) induces physiological, metabolic and behavioral changes. The major hypoxia response pathway is conserved from nematodes to mammals and is driven by activation of the HIF (hypoxia inducible factor) family of transcription factors. Despite a fundamental role of the HIF pathway in regulating cellular homeostasis in response to hypoxic stress, interactions between the HIF pathway and cellular quality-control pathways are largely unknown. Using an unbiased genetic screen, we discovered that in C. elegans nonsense-mediated decay (NMD), an evolutionarily conserved mechanism of RNA surveillance, acts in parallel to HIF-1 to selectively enhance specific aspects of the response to HIF-1 activation, possibly through co-regulation of a distinct subset of HIF-1-upregulated genes. Our findings reveal a functional integration between oxygen sensing and RNA surveillance and establish NMD as a key regulator of specific aspects of the HIF-1-driven transcriptional program and physiological response.

genetics↗

bioRxiv2026

Cohesin and NuRD Antagonistically Drive Alternative Neuronal Fates via PLZF Transcription Factors

Diverse genetic and epigenetic factors cooperate to specify cellular fates during development. Establishing these fates is especially critical in the nervous system, which comprises diverse neuronal cell types. How genomic architecture interfaces with epigenetic regulators to drive transcriptional programs underlying neuronal fates remains poorly understood. Here we show that cohesin, a protein complex that shapes genomic architecture, promotes GABAergic fate specification in a subset of neurons in the nematode Caenorhabditis elegans. This process is facilitated by EOR-1, a homolog of the human promyelocytic leukemia zinc finger (PLZF) transcription factor. The nucleosome remodeling and deacetylase (NuRD) complex and TRA-4, another PLZF homolog, promote tyraminergic fate in the normally GABAergic neurons when cohesin or EOR-1 function is lost, revealing an antagonistic mechanism determining alternative neuronal fates. These findings highlight a critical interplay among genome architecture, epigenetic remodeling and transcriptional regulation in neuronal fate specification and, given the evolutionary conservation of these factors, suggest a mechanism underlying neural development across species. TeaserGenomic architecture, epigenetic and genetic factors interact to determine specific neuronal fates during development.

developmental biology↗

bioRxiv2024

Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation

Hypoxia (low oxygen) activates diverse cellular responses driven primarily by a single transcription factor, the hypoxia-inducible factor HIF-1. Here we identify at single-cell resolution HIF-1-dependent transcriptional responses in neuronal, intestinal, and muscle tissues of the nematode Caenorhabditis elegans. We report that while all three tissues share HIF-1-dependent modulation of pathways for central-carbon metabolism, individual tissues and specific cell subtypes exhibit broader transcriptional responses that differ extensively among cellular contexts. Using supervised machine learning to provide a deeper multivariate analysis, we observed that genotype-defined HIF-1 activation states were distinguishable within each tissue and that the highest-ranked predictive genes varied substantially among tissues. The differential-expression and machine-learning analyses together revealed a hierarchical contextualization of HIF-1-dependent transcriptomes: in response to HIF-1 activation, different tissues express distinct transcriptional programs, and cell subtypes within each tissue express further distinct programs. We validated representative tissue- and cell-type-specific responses in vivo and demonstrated that a gene that is HIF-1-responsive in a specific muscle cell subtype functions in that cell type to regulate HIF-1-driven hypersensitivity to the cholinergic agonist levamisole. Overall, our findings provide a systems-level view of HIF-1 activity and show that a broadly expressed transcription factor can generate both a shared core response and diverse context-dependent transcriptional programs.

genetics↗

bioRxiv2023

Programmed Cell Death Modifies Neural Circuits and Tunes Intrinsic Behavior

Programmed cell death (PCD) is a common feature of animal development. During development of the C. elegans hermaphrodite, programmed cell death eliminates 131 cells in stereotyped positions in the cell lineage, mostly in neuronal lineages. Blocking cell death results in supernumerary "undead" neurons. We find that undead neurons can be wired into circuits, can display activity, and can modify specific behaviors. The two undead RIM-like neurons participate in the RIM-containing circuit that computes movement. The presence of these two extra neurons results in animals that initiate fewer reversals and lengthens the duration of those reversals that do occur. We describe additional behavioral alterations of cell-death mutants, including in locomotory turning angle and pharyngeal pumping. These findings indicate that physiological or evolutionary variations in PCD might reveal latent neuronal elements that the nervous system can incorporate to modify nervous system function and animal behavior.

neuroscience↗

bioRxiv2023

Deletion of VPS50 protein in mice brain impairs synaptic function and behavior

VPS50, is an accessory protein, involved in the synaptic and dense core vesicle acidification and its alterations produce behavioral changes in C.elegans. Here, we produce the mosaic knock out (mKO) of VPS50 using CRISPR/Cas9 system in both cortical cultured neurons and whole animals to evaluate the effect of VPS50 in regulating mammalian brain function and behavior. While mKO of VPS50 does not change the number of synaptic vesicles, it produces a mislocalization of the V-ATPase pump that likely impact in vesicle acidification and vesicle content to impair synaptic and neuronal activity in cultured neurons. In mice, mKO of VPS50 in the hippocampus, alter synaptic transmission and plasticity, and generated robust cognitive impairments associate to memory formation. We propose that VPS50 is an accessory protein that aids the correct recruitment of the V-ATPase pump to synaptic vesicles, thus having a crucial role controlling synaptic vesicle acidification and hence synaptic transmission.

neuroscience↗

bioRxiv2022

A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci

How cells regulate gene expression in a precise spatiotemporal manner during organismal development is a fundamental question in biology. Recent studies have demonstrated the role of transcriptional condensates in gene regulation1-5. However, little is known about the function and regulation of these transcriptional condensates in the context of animal development and physiology. We found that the evolutionarily conserved DEAD-box helicase DDX-23 controls stem cell fate in C. elegans at least in part by binding to and facilitating the condensation of MAB-10, the C. elegans homolog of mammalian NAB protein. MAB-10 is a transcriptional cofactor that functions with the EGR protein LIN-29 to regulate the transcription of genes required for exiting the cell cycle, terminal differentiation, and the larval-to-adult transition6. We suggest that DEAD-box helicase proteins function more generally during animal development to control the condensation of NAB proteins important in cell-fate decisions and that this mechanism is evolutionarily conserved. In mammals, a comparable mechanism might underlie terminal cell differentiation and when misregulated might promote cancerous growth.

genetics↗

bioRxiv2020

An Hourglass Circuit Motif Transforms a Motor Program via Subcellularly Localized Calcium Signaling in Muscle

Neural control of muscle function is fundamental to animal behavior. Many muscles can generate multiple distinct behaviors. Nonetheless, individual muscle cells are generally regarded as the smallest units of motor control. We report that muscle cells can alter behavior by contracting subcellularly. We previously discovered that noxious tastes reverse the net flow of particles through the C. elegans pharynx, a neuromuscular pump, resulting in spitting. We now show that spitting results from the subcellular contraction of the anterior region of the pm3 muscle cell. Subcellularly localized calcium increases accompany this contraction. Spitting is controlled by an "hourglass" circuit motif: parallel neural pathways converge onto a single motor neuron that differentially controls multiple muscles and the critical subcellular muscle compartment. We conclude that subcellular muscle units enable modulatory motor control and propose that subcellular muscle contraction is a fundamental mechanism by which neurons can reshape behavior.

neuroscience↗

bioRxiv2019

Cell cycle S-phase arrest drives cell extrusion

Cell extrusion is a process of cell elimination in which a cell is squeezed out from its tissue of origin. Extrusion occurs in organisms as diverse as sponges, nematodes, insects, fish and mammals. Defective extrusion is linked to many epithelial disorders, including cancer. Despite broad occurrence, cell-intrinsic triggers of extrusion conserved across phyla are generally unknown. We combined genome-wide genetic screens with live-imaging studies of C. elegans embryos and mammalian epithelial cultures and found that S-phase arrest induced extrusion in both. Cells extruded from C. elegans embryos exhibited S-phase arrest, and RNAi treatments that specifically prevent S-phase entry or arrest blocked cell extrusion. Pharmacological induction of S-phase arrest was sufficient to promote cell extrusion from a canine epithelial monolayer. Thus, we have discovered an evolutionarily conserved cell-cycle-dependent trigger of cell extrusion. We suggest that S-phase-arrest induced cell extrusion plays a key role in physiology and disease.

cell biology↗

bioRxiv2017

Neurohormonal signalling controls insulin sensitivity and specificity in C. elegans

Insulin and insulin-like growth factor signalling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. Such responses can be tailored to the environment so that changes in insulin signalling result in distinct physiological responses to different stimuli. For example, the inhibition of insulin-like signalling by osmotic stress or by starvation of C. elegans results in physiologically distinct states and patterns of gene expression. How does insulin-like signalling elicit different responses to different environmental stimuli? We report that neurohormonal signalling involving the C. elegans cytosolic sulfotransferase SSU-1 controls developmental arrest in response to osmotic stress but not to starvation; that SSU-1 functions in a single pair of sensory neurons to control signalling via the nuclear hormone receptor NHR-1; that signalling controlled by SSU-1 acts antagonistically to insulin-like signalling; and that the FOXO transcription factor DAF-16, a downstream effector of insulin-like signalling, enters the nucleus in response to osmotic stress but activates gene expression only if SSU-1 is active. We propose that neurohormonal signalling controlled by one or more cytosolic sulfotransferases similarly regulates the specificity of responses to changes in insulin signalling during periods of environmental stress in other organisms and that abnormalities in such sulfotransferase-controlled neurohormonal signalling might contribute to human disorders that involve insulin signalling, such as obesity and type 2 diabetes.

genetics↗