Biology subjects

Handley, A.

Publications and source records attributed to Handley, A..

8 recordsLinked to original sources

bioRxiv2025

Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress

Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty. One-Sentence SummaryProtecting mitochondria by integrating environmental signals

neuroscience↗

bioRxiv2023

A neuro-intestinal circuit controls mitochondrial dynamics and stress resistance

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. Specific neuropeptidergic signals coordinate the systemic mitochondrial stress response (UPRmt), but whether chemical neurotransmitters also influence this process is unclear. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic 7 receptor. This neuro-intestinal circuit is critical for nonautonomously regulating mitochondrial dynamics and organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses. One-Sentence SummaryRegulation of mitochondrial health with neurotransmission.

neuroscience↗

bioRxiv2023

Nuclear Factor-Y is a Pervasive Regulator of Neuronal Gene Expression

Nervous system function relies on the establishment of complex gene expression programs that provide neuron-type-specific and core pan-neuronal features. These complementary regulatory paradigms are controlled by terminal selector and parallel-acting transcription factors (TFs), respectively. Here, we identify the Nuclear Factor Y (NF-Y) TF as a pervasive regulator of both neuron-type-specific and pan-neuronal gene expression. Mapping global NF-Y targets reveals direct binding to the cis-regulatory regions of pan-neuronal genes and terminal selector TFs. We show that NFYA-1 controls pan-neuronal gene expression directly through binding to CCAAT boxes in target gene promoters and indirectly by regulating the expression of terminal selector TFs. Further, we find that NFYA-1 regulation of neuronal gene expression is important for neuronal activity and motor function. Thus, our research sheds light on how global neuronal gene expression programs are buffered through direct and indirect regulatory mechanisms.

neuroscience↗

bioRxiv2021

Convalescence from prototype SARS-CoV-2 protects Syrian hamsters from disease caused by the Omicron variant

The mutation profile of the SARS-CoV-2 Omicron variant poses a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2, 99.99% identical to Wuhan-Hu-1, to protect against disease caused by the Omicron variant. We established that infection with Omicron in naive Syrian hamsters resulted in a less severe disease than a comparable dose of prototype SARS-CoV-2 (Australia/VIC01/2020), with fewer clinical signs and less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of Omicron 50 days after an initial infection with Australia/VIC01/2020. The data provide evidence for immunity raised against prototype SARS-CoV-2 being protective against Omicron in the Syrian hamster model. Further investigation is required to conclusively determine whether Omicron is less pathogenic in Syrian hamsters and whether this is predictive of pathogenicity in humans.

microbiology↗

bioRxiv2020

Atypical TGF-beta Signaling Controls Neuronal Guidance in Caenorhabditis elegans

Coordinated expression of cell adhesion and signaling molecules is crucial for brain development. Here, we report that the Caenorhabditis elegans transforming growth factor-beta (TGF-{beta}) type I receptor SMA-6 (small-6) acts independently of its cognate TGF-{beta} type II receptor DAF-4 (dauer formation-defective-4) to control neuronal guidance. SMA-6 directs neuronal development from the epidermis through interactions with three, orphan, TGF-{beta} ligands. Intracellular signaling downstream of SMA-6 limits expression of NLR-1, an essential Neurexin-like cell adhesion receptor, to enable neuronal guidance. Together, our data identify an atypical TGF-{beta}-mediated regulatory mechanism to ensure correct development of the nervous system.

developmental biology↗

bioRxiv2019

Diet-responsive Transcriptional Regulation of Insulin in a Single Neuron Controls Systemic Metabolism

To maintain metabolic homeostasis, the nervous system must adapt and respond to an ever-changing environment. Transcription factors are key drivers of this adaptation, eliciting gene expression changes that can alter neuronal activity. Here we show in Caenorhabditis elegans that the terminal selector transcription factor ETS-5 not only establishes the identity of the BAG sensory neurons, but is re-purposed to shape the functional output of the BAG neurons post-mitotically. We find that ETS-5 directly regulates the expression of INS-1, an insulin-like peptide, in the BAG sensory neurons. INS-1 expression in the BAG neurons, and not in other INS-1-expressing neurons, decreases intestinal lipid levels and promotes foraging behaviour. Using in vivo analysis, we show that elevated intestinal lipid stores, driven by a high glucose diet, downregulates ETS-5-driven expression of INS-1. Together, our data reveal an inter-tissue regulatory loop by which a single neuron can control systemic metabolism, and that the activity of this neuron is modulated by the metabolic state of the organism.

genetics↗

bioRxiv2018

Oxygen plasma focused ion beam scanning electron microscopy for biological samples

Over the past decade, gallium Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) has been established as a key technology for cellular tomography. The utility of this approach, however, is severely limited both by throughput and the limited selection of compatible sample preparation protocols. Here, we address these limitations and present oxygen plasma FIB (O-PFIB) as a new and versatile tool for cellular FIB-SEM tomography. Oxygen displays superior resin compatibility to other ion beams and produces curtain-free surfaces with minimal polishing. Our novel approach permits more flexible sample preparation and 30% faster data collection when compared to using gallium ion sources. We demonstrate this alternative FIB is applicable to a variety of embedding procedures and biological samples including brain tissue and whole organisms. Finally, we demonstrate the use of O-PFIB to produce targeted FIB-SEM tomograms through fiducial free en-block correlative light and electron microscopy.

cell biology↗

bioRxiv2018

Protein Disulfide Isomerases Control the Secretion of Wnt proteins

Appropriate Wnt morphogen secretion is required to control animal development and homeostasis. Although correct Wnt globular structure is essential for secretion, proteins that directly mediate Wnt folding and maturation are incompletely characterized. Here, we report that protein disulfide isomerase-1 (PDI-1), a protein folding catalyst and chaperone, controls secretion of the Caenorhabditis elegans Wnt ortholog EGL-20. We find that PDI-1 function is required to correctly form an anteroposterior EGL-20/Wnt gradient during embryonic development. Further, PDI-1 performs this role in EGL-20/Wnt-producing epidermal cells to cell-non-autonomously control EGL-20/Wnt-dependent neuronal migration. Using pharmacological inhibition, we further show that PDI function is required in human cells for Wnt3a secretion, revealing a conserved role for disulfide isomerases. Together, these results demonstrate a critical role for PDIs within Wnt-producing cells to control long-range developmental events that are dependent on Wnt secretion.

developmental biology↗