Biology subjects

Su, C.-Y.

Publications and source records attributed to Su, C.-Y..

14 recordsLinked to original sources

bioRxiv2026

A nanoscale atlas of extracellular vesicles and particles in Drosophila olfactory sensilla

Extracellular particles, including non-vesicular extracellular particles (NVEPs) and extracellular vesicles (EVs), are emerging as key contributors to sensory signaling, yet their ultrastructural organization within native tissues remains underexplored. Native tissues preserve extracellular particle organization and heterogeneity that are often lost during dissociation. Using cryofixation-based serial block-face scanning electron microscopy, we generated a nanoscale atlas of NVEPs and EVs across 352 Drosophila antennal olfactory sensilla ([~]70% coverage). Segmentation of more than 7,800 extracellular particles revealed distinct populations differing in morphology, size, electron density, and sensillum-class distribution. Analyses of EV biogenesis identified multivesicular bodies and membrane budding in auxiliary cells. Furthermore, sensilla housing degenerating neurons exhibited marked accumulation of EVs and NVEPs, accompanied by increased auxiliary-cell EV biogenesis. Together, these findings provide a large-scale ultrastructural characterization of extracellular particles in native sensory tissues and establish a foundation for understanding how extracellular particles are distributed, generated, and function during sensory signaling and degeneration.

neuroscience↗

bioRxiv2026

De Novo Regeneration of Rete Ridges during Cetacean skin wound healing

Humans are tight-skinned mammals who typically fail to regenerate large full-thickness skin wounds, instead healing with substantial scarring and concomitant loss of function. Mechanical context is a major determinant of this outcome: elevated tissue tension or stiffness promotes fibrotic repair associated with hypertrophic or keloid scarring. Accordingly, regenerative medicine research has relied on diverse animal models to understand scar development and skin regeneration. Loose-skinned mammals exhibit greater regeneration ability. Furthermore, spiny mouse skin is significantly less stiff and associated with enhanced regenerative ability. Interestingly, this skin wound stiffness can be modulated to shift healing toward more regenerative or more fibrotic trajectories. Despite of this progress, the restoration of normal skin architecture after large-full thickness injury has not been elucidated in tight-skinned mammals. Can large full-thickness wounds regenerate with minimal scarring in tight-skinned mammals? Here we show the tight-skinned mammal Frasers Dolphin regenerates de novo a complex rete ridge architecture with associated vasculature and minimal scar following large full-thickness wound healing. Counterintuitively, this skin regeneration occurs in an aqueous, high-shear stress and high-tension environment. Complete rete ridge regeneration in tight-skinned mammals has not been documented and not observed in humans except in utero. This unique ability to rebuild elaborate rete ridges under tension is an opportunity to uncover molecular, cellular, and tissue-level mechanisms that enable regenerative wound healing in a mechanical regime typically associated with fibrosis.

pathology↗

bioRxiv2025

Simultaneous recording of spikes and calcium signals in odor-evoked responses of Drosophila antennal neurons

Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for Drosophila ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORNs response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike-calcium response relationships across diverse ORN types.

neuroscience↗

bioRxiv2025

Population-level morphological analysis of paired CO2- and odor-sensing olfactory neurons in D. melanogaster via volume electron microscopy

Dendritic morphology is a defining characteristic of neuronal subtypes. In Drosophila, heterotypic olfactory receptor neurons (ORNs) expressing different receptors display diverse dendritic morphologies, but whether such diversity exists among homotypic ORNs remains unclear. Using serial block-face scanning electron microscopy on cryofixed tissues, we analyzed the majority of CO2-sensing neurons (ab1C) and their odor-sensing neighbors (ab1D) in the D. melanogaster antenna. Surprisingly, ab1C neurons featured flattened, sheet-like dendrites--distinct from the cylindrical branches typical of odor-sensing neurons--and displayed remarkable diversity, ranging from plain sheets to tube-like structures that enclose several neighboring dendrites, forming "dendrite-within-dendrite" structures. Similarly, ab1D dendrites varied from simple, unbranched forms to numerously branched morphologies. These findings suggest that morphological heterogeneity is common even among homotypic ORNs, potentially expanding their functional adaptability and ranges of sensory physiological properties.

neuroscience↗

bioRxiv2024

MR Corge: Sensitivity analysis of Mendelian randomization based on the core gene hypothesis for polygenic exposures

SummaryMendelian randomization is being utilized to assess causal effects of polygenic exposures, where many genetic instruments are subject to horizontal pleiotropy. Existing methods for detecting and correcting for horizontal pleiotropy have important assumptions that may not be fulfilled. Built upon the core gene hypothesis, we developed MR Corge for performing sensitivity analysis of Mendelian randomization. MR Corge identifies a small number of putative core instruments that are more likely to affect genes with a direct biological role in an exposure and obtains causal effect estimates based on these instruments, thereby reducing the risk of horizontal pleiotropy. Using positive and negative controls, we demonstrated that MR Corge estimates aligned with established biomedical knowledge and the results of randomized controlled trials. MR Corge may be widely applied to investigate polygenic exposure-outcome relationships. Availability and ImplementationAn open-sourced R package is available at https://github.com/zhwm/MRCorge.

bioinformatics↗

bioRxiv2023

Shallow networks run deep: Peripheral preprocessing facilitates odor classification

The mammalian brain implements sophisticated sensory processing algorithms along multilayered ( deep) neural-networks. Strategies that insects use to meet similar computational demands, while relying on smaller nervous systems with shallow architectures, remain elusive. Using Drosophila as a model, we uncover the algorithmic role of odor preprocessing by a shallow network of compartmentalized olfactory receptor neurons. Each compartment operates as a ratiometric unit for specific odor-mixtures. This computation arises from a simple mechanism: electrical coupling between two differently-sized neurons. We demonstrate that downstream synaptic connectivity is shaped to optimally leverage amplification of a hedonic value signal in the periphery. Furthermore, peripheral preprocessing is shown to markedly improve novel odor classification in a higher brain center. Together, our work highlights a far-reaching functional role of the sensory periphery for downstream processing. By elucidating the implementation of powerful computations by a shallow network, we provide insights into general principles of efficient sensory processing algorithms.

neuroscience↗

bioRxiv2022

Mutational Changes and Enhanced Cell Migration during Transformation of Breast Non-tumorigenic Cells to Tumorigenic Cells

Although cancer stem cells (CSCs) play a major role in tumorigenesis and metastasis, the role of genetic alterations in invasiveness of CSCs is still unclear. Tumor microenvironment signals, such as extracellular matrix (ECM) composition, significantly influence cell behaviors. Unfortunately, these signals are often lost in in vitro cell culture. This study determines putative CSC populations, examines genetic changes during tumorigenesis of human breast epithelial stem cells, and investigates single-cell migration properties on ECM-mimetic platforms. Whole exome sequencing data indicate that tumorigenic cells have a higher somatic mutation burden than non-tumorigenic cells, and that mutations exclusive to tumorigenic cells exhibit higher predictive deleterious scores. Tumorigenic cells exhibit distinct somatic copy number variations (CNVs) including gain of duplications in chromosomes 5 and 8. ECM-mimetic topography selectively enhances migration speed of tumorigenic cells, but not of non-tumorigenic cells, and results in a wide distribution of tumorigenic single-cell migration speeds, suggesting heterogeneity in cellular sensing of contact guidance cues. This study identifies mutations and CNVs acquired during breast tumorigenesis, which can be associated with enhanced migration of breast tumorigenic cells, and demonstrates that a nanotopographically-defined platform can be applied to recapitulate an ECM structure for investigating cellular migration in the simulated tumor microenvironment.

cancer biology↗

bioRxiv2022

Comparative transcriptomics of the Drosophila olfactory subsystems identifies a support cell-expressed Osiris protein required for pheromone sensing

The nose of most animals comprises multiple sensory subsystems, which are defined by the expression of different olfactory receptor families. Drosophila melanogaster antennae comprise two morphologically and functionally distinct subsystems that express Odorant receptors (Ors) or Ionotropic receptors (Irs). Although these receptors have been thoroughly characterized in this species, the subsystem-specific expression and roles of other genes are much less well-understood. Here we generate subsystem-specific transcriptomic datasets to identify hundreds of genes, encoding diverse protein classes, that are selectively enriched in either Or or Ir subsystems. Using single-cell antennal transcriptomic data and RNA in situ hybridization, we find most neuronal genes - other than sensory receptor genes - are broadly expressed within the subsystems. By contrast, we identify many non-neuronal genes that exhibit highly selective cell-type expression, revealing substantial molecular heterogeneity in the non-neuronal cellular components of these olfactory subsystems. We characterize one Or subsystem-specific non-neuronal molecule, Osiris 8 (Osi8), a conserved member of a large family of insect transmembrane proteins. Osi8 is expressed in tormogen support cells that are associated with pheromone sensing neurons. Loss of Osi8 abolishes high sensitivity neuronal responses to pheromone ligands. Together this work identifies a new protein required for insect pheromone detection, emphasizes the importance of support cells in sensory responses, and provides a resource for future characterization of other olfactory subsystem-specific genes.

neuroscience↗

bioRxiv2021

Systematic morphological and morphometric analysis of identified olfactory receptor neurons in Drosophila melanogaster

The biophysical properties of sensory neurons are influenced by their morphometric and morphological features, whose precise measurements require high-quality volume electron microscopy (EM). However, systematic surveys of these nanoscale characteristics for identified neurons are scarce. Here, we characterize the morphology of Drosophila olfactory receptor neurons (ORNs) across the majority of genetically identified sensory hairs. By analyzing serial block-face electron microscopy (SBEM) images of cryofixed antennal tissues, we compile an extensive morphometric dataset based on 122 reconstructed 3D models of 33 identified ORN types. In addition, we observe multiple novel features--including extracellular vacuoles within sensillum lumen, intricate dendritic branching, mitochondria enrichment in select ORNs, novel sensillum types, and empty sensilla containing no neurons--which raise new questions pertinent to cell biology and sensory neurobiology. Our systematic survey is critical for future investigations into how the size and shape of sensory neurons influence their responses, sensitivity and circuit function.

neuroscience↗

bioRxiv2021

An ammonium transporter is a non-canonical olfactory receptor for ammonia

Two families of ligand-gated ion channels function as olfactory receptors in insects. Here, we show that these canonical olfactory receptors are not necessary for responses to ammonia, a key ecological odor that is attractive to many insects including disease vectors and agricultural pests. Instead, we show that a member of the ancient electrogenic ammonium transporter family, Amt, is a new type of olfactory receptor. We report two hitherto unidentified olfactory neuron populations that mediate neuronal and behavioral responses to ammonia. Their endogenous ammonia responses are Amt-dependent, and ectopic expression of either Drosophila or Anopheles Amt confers ammonia sensitivity. Amt is the first transporter known to function as an olfactory receptor in animals, and its role may be conserved across insect species.

neuroscience↗

bioRxiv2018

Chimpanzee SIV Envelope trimer: structure and deployment as an HIV vaccine template

Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. Chimpanzee SIV Envelope (Env) shares a single bnAb site, the V2-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Accordingly, we generated a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determined the structure of the MT145K trimer by cryo-EM and showed its architecture was remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knock-in mouse with chimpanzee MT145K trimer induced HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induced responses exhibiting some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs.

immunology↗

bioRxiv2018

Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons

In the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this unusual form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to prove that direct electrical (\"ephaptic\") interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.

neuroscience↗

bioRxiv2018

High-quality ultrastructural preservation using cryofixation for 3D electron microscopy of genetically labeled tissues

Electron microscopy (EM) offers unparalleled power to study cell substructures at the nanoscale. Cryofixation by high-pressure freezing offers optimal morphological preservation, as it captures cellular structures instantaneously in their near-native states. However, the applicability of cryofixation is limited by its incompatibilities with diaminobenzidine labeling using genetic EM tags and the high-contrast en bloc staining required for serial block-face scanning electron microscopy (SBEM). In addition, it is challenging to perform correlated light and electron microscopy (CLEM) with cryofixed samples. Consequently, these powerful methods cannot be applied to address questions requiring optimal morphological preservation and high temporal resolution. Here we developed an approach that overcomes these limitations; it enables genetically labeled, cryofixed samples to be characterized with SBEM and 3D CLEM. Our approach is broadly applicable, as demonstrated in cultured cells, Drosophila olfactory organ and mouse brain. This optimization exploits the potential of cryofixation, allowing quality ultrastructural preservation for diverse EM applications.

biophysics↗

bioRxiv2017

Multiple zebrafish atoh1 genes specify a diversity of neuronal types in the zebrafish cerebellum

The basic Helix-Loop-Helix transcription factor Atoh1 is required for the specification of multiple neuron types in the mammalian hindbrain including tegmental, precerebellar output neurons and cerebellar granule neurons. How a single proneural gene specifies so many neuron types from a single progenitor zone, the upper rhombic lip (URL), is not known. Here we use the zebrafish to explore the role of atoh1 in cerebellar neurogenesis. Using transgenic reporters we show that zebrafish atoh1c-expressing cells give rise to tegmental and granule cell populations that, together with previously described atoh1a-derived neuron populations, resemble the diversity of atoh1 derivatives observed in mammals. Using genetic mutants we find that of the three zebrafish atoh1 paralogs, atoh1c and atoh1a are required for the full complement of granule neurons in the zebrafish cerebellum. Interestingly, atoh1a and atoh1c specify non-overlapping granule populations, indicating that fish use multiple atoh1 genes to generate granule neuron diversity that is not detected in mammals. By live imaging of neurogenesis at the URL we show that atoh1c is not required for the specification of granule neuron progenitors but promotes their delamination from the URL epithelium and this process is critical for neuronal maturation. This study thus provides a better understanding of how proneural transcription factors regulate neurogenesis in the vertebrate cerebellum.\n\nSummary statementatoh1 genes specify distinct populations of tegmental and granule neurons in the zebrafish hindbrain and promote their delamination from the neuroepithelium, a process critical for neuronal maturation.

developmental biology↗