Biology subjects

Lee, K.-S.

Publications and source records attributed to Lee, K.-S..

12 recordsLinked to original sources

bioRxiv2026

Understanding cephalopod regeneration: impact of sexual maturation, injury severity and general anesthesia on octopus arm restoration

Octopuses exhibit remarkable regenerative capacity, as shown by their ability to fully restore a whole arm. During this process, a complex appendage containing muscle, connective tissue, vasculature, suckers, sensory structures, peripheral nerves and the axial nerve cord (ANC) is regrown. Although the morphology of octopus regeneration is increasingly well described, the physiological variables that determine regenerative speed, including the potential contribution of ion-channel-dependent processes, remain poorly understood. In this work we examined the influence of reproductive state, injury severity, biological sex and magnesium chloride (MgCl2) anesthesia, on the rate of longitudinal arm regrowth. Reproductive stage was the strongest determinant of regenerative performance: pre-reproductive stage (pre-RS) animals showed robust regrowth, whereas reproductive stage (RS) animals regenerated significantly slower. In pre-RS animals, regeneration speed scaled strongly with injury severity, whereas this relationship was absent in RS animals. Biological sex did not independently predict regeneration speed, and MgCl2 exposure showed no long-term inhibitory effect on regeneration. Our final model explained 81.4% of variance in regeneration speed, with reproductive state and injury severity having major effects. These findings demonstrate that sexual maturation and optic-gland-mediated senescence act as an irreversible physiological block against somatic regeneration, and provide empirical support for mechanosensory and bioelectric-dependent scaling models of cephalopod limb restoration.

neuroscience↗

bioRxiv2026

Annual life-history strategy hitchhikes low-light adaptation in a clonal seagrass

While life-history strategies are typically fixed within species, evolutionary transitions between perenniality and annuality can occur. In clonal seagrasses, annual and perennial plants often coexist in the same population, providing a unique model for studying the genetic basis of this transition. Two seagrass Zostera marina populations in South Korea display a striking dichotomy: shallow-water sub-populations follow a typical perennial strategy, whereas their deep-water counterparts are annual. Here we show that this shift from perenniality to annuality, potentially caused by the SAPK7 gene, is genetically coupled with the CAO gene, which is under strong positive selection for low-light adaptation. The up-regulation of the SAPK7 gene triggers early flowering in seedlings, before the formation of any lateral shoots via asexual reproduction. In this special case where the genet contains only one ramet, the post-reproductive death of the ramet is equivalent to the death of the whole genet, which explains the annual phenotype. Our findings reveal a mechanistic example where annuality overcomes perenniality by hitchhiking on a positively selected gene. Given that the ancestral state of plants is perennial, this coupling of annuality with beneficial alleles may represent one of the pathways for the repeated evolution of annual life histories across flowering plants.

evolutionary biology↗

bioRxiv2024

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXTs downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.

cancer biology↗

bioRxiv2024

Lamellar Schwann cells in the Pacinian corpuscle potentiate vibration perception

Pacinian corpuscles are among the most sensitive mechanoreceptors found in vertebrates and they are tuned to vibrations in the highest perceptible frequency range (100-2000Hz). One of their anatomical hallmarks is the onion-like cell layers surrounding the central axon. The innermost layers consist of [~]60 densely packed lamellar Schwann cells (LSCs), whose function remains largely unknown. Using high-resolution 3D electron microscopy we found that LSCs in Pacinian corpuscles of the mouse hindlimb do not form concentric rings, but complex, multilayered and intertwining assemblies that are connected via an estimated 5805.1 desmosomes and 4142.5 gap-junctions. LSCs make multiple converging contacts with the afferent axon and its protrusions with desmosomes. Using optogenetic manipulations of LSCs we demonstrate that their activation does not only drive reliable time-locked spiking in the axon, but that their inactivation significantly elevates the thresholds in-situ and increases perceptual thresholds behaviorally. Together these findings provide evidence that LSCs are a key element of somatosensory processing, actively potentiating mechanosensitivity in Pacinian corpuscles. HighlightsO_LIHigh-resolution electron microscopy reveals details of the Pacinian corpuscle C_LIO_LILamellar Schwann cells form claw-like structures with converging axonal contacts C_LIO_LISchwann-cell modulation bidirectionally affects neural coding of Pacinian afferent C_LIO_LIInactivation of lamellar Schwann-cells increases perceptual thresholds C_LI

neuroscience↗

bioRxiv2023

Transformation of neural coding for vibrotactile stimuli along the ascending somatosensory pathway

Perceiving substrate vibrations is a fundamental component of somatosensation. In mammals, action potentials fired by rapidly adapting mechanosensitive afferents are known to reliably time lock to the cycles of a vibration. This stands in contrast to coding in the higher-order somatosensory cortices, where neurons generally encode vibrations in their firing rates, which are tuned to a preferred vibration frequency. How and where along the ascending neuraxis is the peripheral afferent temporal code of cyclically entrained action potentials transformed into a rate code is currently not clear. To answer this question, we probed the encoding of vibrotactile stimuli with electrophysiological recordings along major stages of the ascending somatosensory pathway in mice. Recordings from individual primary sensory neurons in lightly anesthetized mice revealed that rapidly adapting mechanosensitive afferents innervating Pacinian corpuscles display phase-locked spiking for vibrations up to 2000 Hz. This precise temporal code was reliably preserved through the brainstem dorsal column nuclei. The main transformation step was identified at the level of the thalamus, where we observed a significant loss of phase-locked spike timing information accompanied by a further narrowing of tuning curve widths. Using optogenetic manipulation of thalamic inhibitory circuits, we found that parvalbumin-positive interneurons in thalamic reticular nucleus participate in sharpening frequency selectivity and disrupting the precise spike timing of ascending neural signals encoding vibrotactile stimuli. To test the functional implications of these different neural coding mechanisms, we applied frequency-specific microstimulation within the brainstem, which generated frequency selectivity reminiscent of real vibration responses in the somatosensory cortex, whereas microstimulation within thalamus did not. Finally, we applied microstimulation in the brainstem of behaving mice and demonstrated that frequency-specific stimulation could provide informative and robust signals for learning. Taken together, these findings not only reveal novel features of the computational circuits underlying vibrotactile sensation, but could also guide biomimetic stimulus strategies to activate specific nuclei along the ascending somatosensory pathway for sensory neural prostheses.

neuroscience↗

bioRxiv2023

Emergence of a somatosensory tonotopic map for substrate vibration in the brainstem

Perceiving substrate vibrations is a fundamental component of tactile perception. The wide frequency spectrum of vibrations is covered by integrating responses of multiple mechanoreceptors that innervate various subtypes of mechanosensitive end organs, each preferring a specific range: Merkel cells (0.5-10Hz), Meissner corpuscles (10-150Hz) and Pacinian corpuscles (150-1000Hz) in primates. As the density of different end organs greatly varies across the body, each body part potentially has a specific frequency preference. How location (somatotopy) and frequency tuning (tonotopy) are processed along the ascending neuraxis and how they converge to drive responses of individual neurons is poorly understood. In this study, we address this question by combining in vivo peripheral electrophysiology and two-photon calcium imaging along the entire dorsal column-medial lemniscal pathway, including the dorsal root ganglia, dorsal column nuclei (DCN), the thalamus and the cortex. Surprisingly, we found that both frequency, as well as location, are organised into structured maps in the DCN. Furthermore, both maps are intimately related at the fine spatial scale with parallel map gradients that are consistent across the depth of the DCN and preserved along the ascending pathway. Additional sensory mapping experiments based on peripheral characterisation revealed that the tonotopic map only partially reflects the distribution of end organs in the skin and deep tissue. Instead, we show that the emergence of the finescale tonotopy is probably due to the selective dendritic sampling from axonal afferents, right at the first synaptic relay. Taken together, we conclude DCN neural circuits are key to the emergence of these two fine-scale topological organisations in early somatosensory pathways. The underlying computational principle is intriguingly similar to the integration of multiple functional maps along the ascending visual pathways, suggesting a universal law governing the optimization of sensory systems.

neuroscience↗

bioRxiv2023

Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions

Linking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception. SIGNIFICANCEMost rare cancers are poorly understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. This study illustrates the potential of linking precision oncology programs with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers that could improve the clinical management of such diseases.

cancer biology↗

bioRxiv2022

Trogocytic-molting of T-cell microvilli controls T-cell clonal expansion

Internalization of the T-cell antigen receptor (TCR) is intimately linked to T-cell activation: a phenomenon thought to be related to the "exhaustion" of T-cell responses. To date, however, no report has considered that during physical interaction with cognate antigen-presenting cells, T cells release many TCRs via T-cell microvilli particles, which are derived from finger-like membrane structures (microvilli) in a combined process of trogocytosis and enzymatic vesiculation and correspond with the loss of membrane TCRs and many external membrane components. Surprisingly, in contrast to TCR internalization, this event leads to rapid upregulation of surface TCRs and remarkable metabolic reprogramming of cholesterol and fatty acids synthesis to meet the demands of clonal expansion, which drives multiple rounds of division and cell survival. We called this event "trogocytic-molting," which represents an intrinsic molecular basis of T-cell clonal expansion by which T cells gain increased sensitivity to low antigen concentrations. TEASER"Trogocytic-molting," led to the rapid upregulation of surface TCRs and tremendous metabolic reprogramming to meet the demands of clonal expansion.

immunology↗

bioRxiv2021

Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing's syndrome

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushings syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushings mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushings variant promotes the transmission of a distinct downstream pathogenic signal.

molecular biology↗

bioRxiv2020

A sinusoidal transform of the visual field in cortical area V2

The retinotopic maps of many visual cortical areas are thought to follow the fundamental principles that have been described for primary visual cortex (V1) where nearby points on the retina map to nearby points on the surface of V1, and orthogonal axes of the retinal surface are represented along orthogonal axes of the cortical surface. Here we demonstrate a striking departure from this conventional mapping in the secondary visual area (V2) of the tree shrew. Although local retinotopy is preserved, orthogonal axes of the retina are represented along the same axis of the cortical surface, an unexpected geometry explained by an orderly sinusoidal transform of the retinal surface. This sinusoidal topography is ideally suited for achieving uniform coverage in an elongated area like V2, is predicted by mathematical models designed to achieve wiring minimization, and provides a novel explanation for stripe-like patterns of intra-cortical connections and stimulus response properties in V2. Our findings suggest that cortical circuits flexibly implement solutions to sensory surface representation, with dramatic consequences for the large-scale layout of topographic maps.

neuroscience↗

bioRxiv2020

Common computational principle for vibro-tactile pitch perception in mouse and human

We live surrounded by vibrations generated by moving objects. These oscillatory stimuli can produce sound (i.e. airborne waves) and propagate through solid substrates. Pitch is the main perceptual characteristic of sound, and a similar perceptual attribute seems to exist in the case of substrate vibrations: vibro-tactile pitch. Here, we establish a mechanistic relationship between vibro-tactile pitch perception and the actual physical properties of vibrations using behavioral tasks, in which vibratory stimuli were delivered to the human fingertip or the mouse forelimb. The resulting perceptual reports were analyzed with a model demonstrating that physically different combinations of vibration frequencies and amplitudes can produce equal pitch perception. We found that the perceptually indistinguishable but physically different stimuli follow a common computational principle in mouse and human. It dictates that vibro-tactile pitch perception is shifted with increases in amplitude toward the frequency of highest vibrotactile sensitivity. These findings suggest the existence of a fundamental relationship between the seemingly unrelated concepts of spectral sensitivity and pitch perception.

neuroscience↗

bioRxiv2018

Vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signaling in zebrafish

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors and vascular anomalies in DS patients suggests a role of DYRK1A in angiogenesis, but in vivo evidence is lacking. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in the cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that dyrk1aa plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.

developmental biology↗