Biology subjects

Miura, M.

Publications and source records attributed to Miura, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Dopaminergic tone predicts rhythmic temporal attention in Parkinson's disease

Beat perception, the ability to perceive and anticipate a regular pulse in music, is thought to depend on the basal ganglia. Dopaminergic signaling is a candidate mechanism given its prominence in basal ganglia circuitry and established function in encoding temporal predictions. Parkinson's disease (PD) provides a model for studying dopaminergic contributions to beat perception. To test the hypothesis that higher dopaminergic tone is associated with better beat perception, we conducted a study in PD patients (n=55) and matched controls (n=53). Participants performed a musical beat perception task, the Beat Drop Alignment Test (BDAT). They also completed a non-timing control task measuring musical pitch perception, the Mistuning Perception Test (MPT). We identified a double dissociation in PD patients: daily dopamine dose was associated with beat perception (r=.37, p=.005) but not pitch perception (r=.12, p=.397), while musical background was associated with pitch perception (r=.55, p<.001) but not beat perception (r=.16, p=.236). Results remained consistent when controlling for disease duration and age. This dissociation suggests the effect of dopamine is specific to beat perception and not reflective of a general improvement in auditory processing. High-dopamine patients outperformed both low-dopamine patients and age-matched controls, and this difference was driven by better detection of on-beat than off-beat events. Together, these results suggest that dopamine is associated with enhanced beat perception, potentially through modulation of temporal attention to expected beat times.

neuroscience↗

bioRxiv2026

A reabsorption mechanism in Drosophila renal tubules maintains amino acid homeostasis

The kidney plays a central role in maintaining systemic homeostasis by regulating the excretion of metabolic compounds. In mammals, this is achieved through filtration followed by selective reabsorption, whereas insect Malpighian tubules (MTs) are thought to function primarily through active secretion. Although reabsorption of ions and water has been described in MTs, whether these tissues regulate metabolite balance through reabsorption remains unclear. Here, we uncover an amino acid (AA) reabsorption mechanism in Drosophila MTs. Quantification of AAs in excreta reveals that AA excretion changes rapidly and markedly in response to dietary protein levels, while systemic AA levels remain stable. Using ex vivo assays, we show that MTs actively transport AAs. We identify the AA transporter Slimfast (Slif), expressed in the lower tubule, as a key mediator required to maintain systemic levels of basic AAs. These findings reveal a previously unrecognised reabsorption-based strategy in insect renal tubules that functionally parallels mammalian kidney physiology, despite their distinct organisation. Our study demonstrates that AA excretion forms an additional layer to achieve metabolic homeostasis.

physiology↗

bioRxiv2026

Division of labor between ERK and Notch signaling coordinates distinct stem cell populations during jellyfish tentacle regeneration

Regeneration restores lost tissues through diverse cellular strategies that vary across species and tissue contexts. In many systems, regeneration involves blastema formation; however, how blastema formation is coordinated in tissues employing multiple stem/progenitor populations remains unclear. Here, we investigate tentacle regeneration in the hydrozoan jellyfish Cladonema, in which two distinct proliferative populations contribute to regeneration: resident homeostatic stem cells (RHSCs), which supply differentiated cell types, and repair-specific proliferative cells (RSPCs), which are transiently induced upon injury to form the blastema. While extensive cell death occurs shortly after injury, it is largely dispensable for blastema formation. Using pharmacological inhibition and cell proliferation analyses, we identify ERK/MAPK signaling as a key regulator of blastema formation. ERK signaling is rapidly activated at the injury site and selectively promotes proliferation of RSPCs without affecting RHSC proliferation. In contrast, inhibition of Notch signaling disrupts nematocyte differentiation and induces hyperproliferation of RHSCs, while leaving RSPC proliferation unchanged, indicating that Notch signaling governs the balance between differentiation and self-renewal in RHSCs. Together, these findings reveal a division of labor between conserved signaling pathways and support a model in which regeneration is achieved through spatially and functionally compartmentalized control of distinct stem cell populations.

developmental biology↗

bioRxiv2026

Aging disrupts tissue homeostasis and constrains blastema-mediated regeneration in the Cladonema medusa

Regenerative capacity varies widely across animals, yet aging is often accompanied by declining tissue homeostasis and regenerative potential. In many species, regeneration of complex structures relies on epimorphic programs that form a blastema, coordinating cell proliferation and pattern reorganization after injury. Although aging-associated regeneration defects have been documented in several bilaterian models, how aging shapes regeneration in early-branching metazoans with robust regenerative abilities remains unclear. Here, we investigate aging and regeneration in the medusa stage of Cladonema pacificum, a cnidarian that retains high regenerative capacity within a finite lifespan. We show that aging in Cladonema medusae is accompanied by progressive morphological and functional deterioration, including shrinkage of the umbrella and manubrium, tentacle shortening, and reduced reproductive output, along with increased DNA damage. At the cellular level, aging is associated with depletion of differentiated cell populations, including nematocytes and neurons, as well as reductions in stem cell-associated populations and proliferative activity in the tentacle bulb. Consistent with these changes, tentacle regeneration is markedly impaired in aged medusae and is characterized by delayed wound closure, defective blastema formation, and incomplete functional recovery. Together, our findings indicate that aging disrupts both tissue homeostasis and blastema-mediated regeneration in Cladonema medusae, establishing a tractable model for studying aging-regeneration interactions and supporting the view that aging imposes broadly shared constraints on regenerative systems across metazoans.

developmental biology↗

bioRxiv2025

Bruce suppresses autophagy-regulated caspase activity and wing tissue growth in Drosophila

Caspases are cysteine-aspartic proteases that mediate both lethal and non-lethal cellular outcomes, including the promotion of tissue growth. However, the mechanisms underlying the differential regulation of these activities remain unclear. We have previously shown that among the two Drosophila executioner caspases, Dcp-1 and Drice, Dcp-1 promotes tissue growth in a non-lethal manner, independent of canonical apoptotic signaling. Herein, we demonstrated that overexpressed Dcp-1, but not Drice, was activated without canonical apoptosome components. TurboID-based proximity labeling revealed distinct proximal proteomes, among which Sirtuin 1, an Atg8a deacetylase, which promotes autophagy, was specifically required for Dcp-1 activation. Autophagy-related genes, including Bcl-2 family members Debcl and Buffy, are required for Dcp-1 activation. Structure-based prediction using AlphaFold3 further identified Bruce, an autophagy-regulated inhibitor of apoptosis, as a Dcp-1-specific regulator acting outside the apoptosome-mediated pathway. Physiologically, Bruce suppresses wing tissue growth. These findings indicate that non-lethal Dcp-1 activity is governed by the autophagy-Bruce axis, enabling distinct non-lethal functions independent of cell death.

developmental biology↗

bioRxiv2025

Genome-wide association study shows developmental robustness control by intestinal maltase via internal environment in Drosophila

Organisms encounter disturbances during development because of genetic variations, environmental shifts, and stochastic noise. However, developmental robustness and canalization buffer these fluctuations to maintain normal development. Nevertheless, understanding the underlying mechanisms that govern this robustness is challenging because of the complex interactions between these factors. In Drosophila, the number of scutellar sensory organs (SSO; macrochaetes) derived from the sensory organ precursors (SOPs) in the larval wing disc has been used as a model to study developmental robustness. Although the number of SOPs is strictly regulated by a network of signaling and transcription factors in the imaginal disc, non-intrinsic broader factors such as temperature and energy metabolism additionally influence SSO-number fluctuation. Moreover, the precise molecular mechanisms regulating the systemic control of bristle number remain unknown. In this study, we identify factors controlling bristle robustness by performing genome-wide association studies (GWAS). We observed significant single-nucleotide polymorphisms (SNPs) in the Maltase gene cluster and found that the knockdown of Maltase genes affected SSO numbers. Furthermore, Maltase-A1(Mal-A1) in the gut regulated insulin signaling systemically, thereby affecting SSO-number fluctuation. These results suggest that Mal-A1 contributes to robustness by modulating glucose availability and Drosophila insulin-like peptide 3 (dilp3) level, which affects the SOPs in a nonautonomous manner. This study presents the molecular basis of nutritional regulation of developmental robustness and highlights Maltase as a key mediator.

developmental biology↗

bioRxiv2025

Hippo-activated cells induce non-cell autonomous tumorigenesis in Drosophila

The Hippo pathway is known as a tumor-suppressor pathway, and most related studies have indicated that the inhibition of the Hippo pathway leads to tumorigenesis. However, recent studies have suggested that the activated Hippo pathway can potentially promote tumorigenesis in some contexts. Here, we show that the activated Hippo pathway induces non-cell-autonomous tumorigenesis characterized by tumor markers in the Drosophila wing epithelium. This suggests that the Hippo-activated cells behave similarly to "oncogenic niche cells." We found that the Hippo-activated cells distantly induced tumor-like cells exhibiting aberrant cell proliferation. Moreover, we identified the evolutionarily conserved amino acid transporters, Sat1/2, that redundantly work with the growth factors, Wingless and Spitz, for non-cell autonomous tumorigenesis. Our findings provide novel insights into the Hippo pathway and may be useful in developing cancer treatments targeting the Hippo pathway.

cell biology↗

bioRxiv2025

Repressive S-adenosylmethionine biosynthesis status inhibits transcription of HeT-A retrotransposon in the germline of Drosophila.

S-adenosylmethionine (SAM) is the principal cellular donor of methyl moiety in the methylation reaction and regulates gene expression by regulating methylation-related cellular events, such as epigenetic status. Although SAM biosynthesis affects a variety of biological phenomena including disease and aging, whether cell-specific SAM biosynthesis status is present and how it contributes to cellular function are largely unknown. Here, we firstly showed that the Drosophila germline in gametogenesis has a repressive SAM biosynthesis status through the observation of SAM synthetase (Sam-S), a key enzyme for SAM biosynthesis. In addition, our study showed that germline-unique repressive SAM biosynthesis status contributes to inhibition of retrotransposon expression; enhancement of SAM biosynthesis in germline caused excessive expression of retrotransposons including HeT-A, a telomere-specific retroelement, as the most affected target. We found that the promoter activity of HeT-A is enhanced in SAM increased condition with increased accumulation of 6mA DNA methylation, the major DNA methylation modification in the Drosophila genome. Interestingly, the enhanced 6mA enrichment and gene expression in enriched loci were not correlated in other retrotransposons or structural genes. Taken together, our results suggest that SAM-deficient status in the germline uniquely regulates HeT-A transcription via 6mA methylation modification. Thus, our study provides a new understanding of how germline unique metabolic status contributes to regulation of the retrotransposon.

developmental biology↗

bioRxiv2025

Early-peaking caspase-7 activity at the plasma membrane drives apoptotic phosphatidylserine exposure

Apoptosis is an immunologically silent form of regulated cell death executed by caspase1. Caspase cleaves hundreds of substrates throughout the cell to regulate apoptotic processes2, including phosphatidylserine (PS) externalization3-5. However, spatio-temporal regulation of caspase activity in dying cells remains unclear. Here, we show that caspase activity peaks earlier at the plasma membrane (PM) during apoptosis by establishing a Dual Forster resonance energy transfer (Dual FRET) imaging system that combines subcellularly targeted FRET-based caspase biosensors with a cytosolic reference counterpart6,7. Genetic analysis identified caspase-7, an executioner caspase considered an inefficient backup for caspase-3, the major executioner caspase8,9, as a caspase responsible for the Early-Peaking Caspase Activity at the PM (EP-CAP). Mechanistically, EP-CAP is mediated via electrostatic interactions between PS in the inner leaflet of the PM and polybasic residues in the N-terminal intrinsically disordered region (IDR) of caspase-7, which are liberated by the caspase-mediated removal of polyacidic residues. Physiologically, EP-CAP facilitates the efficient cleavage of phospholipid scramblases for the rapid externalization of PS and subsequent efferocytosis. Accordingly, we propose that caspase-7, but not caspase-3, is a bona fide immunologically silent death caspase reinforcing the non-inflammatory nature of apoptosis via EP-CAP.

cell biology↗

bioRxiv2025

BubR1 and Mad2 regulate adult midgut remodeling in Drosophila diapause

Diapause is a survival strategy in which growth and aging are temporarily suspended, enabling animals to withstand unfavorable environments. Various insects, including the fruit fly Drosophila, enter reproductive diapause, or dormancy, in response to colder temperatures and/or shorter day lengths. During reproductive diapause, ovarian development halts, and non-reproductive organs also undergo remodeling at both morphological and metabolic levels: however, the mechanisms underlying this remodeling and its physiological impact remain largely unclear. Here, we show that the Drosophila adult midgut undergoes extensive remodeling in diapause, marked by a sustained suspension of growth due to the cell cycle arrest of intestinal stem cells (ISCs) that revert to normal upon returning to recovery conditions. During dormancy, BubR1 and Mad2, key regulators of mitosis, are highly expressed and localized in the cytoplasm of ISCs rather than at the kinetochore, and both BubR1 and Mad2 are essential for diapause-specific midgut remodeling. Furthermore, disruption of midgut growth arrest during diapause reduces the resistance to starvation in adult flies. Together, our findings identify a novel role for BubR1 and Mad2 in ISCs-promoting proper midgut remodeling during dormancy-and highlight the importance of this process for survival under adverse environments.

developmental biology↗

bioRxiv2024

Secretome analysis by proximal labeling in Golgi apparatus for identifying fat body derived humoral factors in Drosophila disc regeneration

Humoral factors act as inter-tissue mediators and regulate various organismal physiologies. Although the importance of humoral factors in tissue repair has been recently recognized, our understanding of how humoral proteins regulate tissue repair remains limited. Glycosylation is an important modification of the conventional secretory pathway, and we have demonstrated that N-glycosylation in the Golgi apparatus of the Drosophila fat body (FB), the major secretory tissue equivalent to the mammalian liver and adipose tissue, remotely contributes to epithelial tissue repair. To identify humoral factors that contribute to repair via the Golgi apparatus, we constructed a Golgi-specific protein biotinylation system and performed hemolymph proteomics. By combining genetic analyses, we found that FB-derived innate immune regulators and iron mediators affect tissue repair. Altogether, our Golgi-specific labeling system has the potential to identify Golgi-mediated secreted factors that regulate inter-organ communication.

developmental biology↗

bioRxiv2024

Dietary zinc restriction mimics protein restriction and extends lifespan in Drosophila

Dietary restriction extends lifespan in model organisms, mainly through dietary amino acids. Compared to macronutrients, the effect of dietary micronutrients on organismal lifespan has not been intensively investigated. Here, using a synthetic diet, we test whether restriction of each micronutrient, including vitamins and minerals, affects lifespan and fecundity in adult Drosophila. While restriction of many of these micronutrients have either negative or no impact on lifespan, zinc (Zn) restriction alone can increase it. Dietary Zn restriction (ZnR) decreases fecundity, increases starvation resistance, and promotes preference for feeding amino acids, in adult females, phenocopying dietary amino acid restriction. Our study demonstrates that dietary intake of trace elements has profound impacts on physiology and lifespan, and that limiting dietary zinc may be a strategy to improve the healthspan of animals.

physiology↗

bioRxiv2024

S-adenosylmethionine metabolism buffering is regulated by glycine N-methyltransferase decrease via nuclear ubiquitin-proteasome system

Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) of Drosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin-proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt degradation by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated degradation helps maintain SAM levels under SAM shortage conditions. Significance StatementS-adenosylmethionine (SAM) metabolism is crucial for diverse functions, which are mediated through methylation process. Although the feedback regulation of SAM production has been explored extensively, our understanding of the mechanism behind SAM consumption remains incomplete. Constant levels of SAM have been observed in Drosophila fat bodies even under conditions of SAM shortage, including nutrient deficiency and inhibition of SAM synthesis. SAM levels are controlled by the degradation of glycine N-methyltransferase (Gnmt), a cytosolic SAM-consuming enzyme, via the nuclear ubiquitin-proteasome system under conditions of SAM shortage. Additionally, the inhibition of Gnmt degradation by suppression of the nuclear UPS causes starvation tolerance. Considering that SAM accumulation promotes energy expenditure in vivo, the starvation-dependent mechanism of Gnmt degradation is important for energy homeostasis.

molecular biology↗

bioRxiv2024

A Nonsecretory Antimicrobial Peptide Mediates Inflammatory Organ Damage in Drosophila Renal Tubules

An excessive immune response damages organs, yet its molecular mechanism is incompletely understood. In this study, we used Drosophila renal tubules as a model to screen a factor mediating organ damage upon genetic activation of an innate immune Imd signalling pathway. We identified an antimicrobial peptide, Attacin-D (AttD), which causes organ damage upon Imd activation in the Malpighian tubules. Loss of AttD function suppresses most of the pathological phenotypes induced by Imd activation, such as cell death, compensatory stem cell proliferation, bloating of whole animal, susceptibility to a high salt diet, elevation of purine levels, and mortality, without compromising the immune activation. AttD is required for the immune-induced damage specifically in the Malpighian tubules but not the midgut. Interestingly, AttD uniquely lacks the signal peptide and is not secreted out from cells. Suppression of AttD almost completely attenuates mortality induced by gut tumour-induced immune activation. Our study elucidates the mechanistic effector of immune-induced organ damage.

immunology↗

bioRxiv2024

Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway

Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via 7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors.

cell biology↗

bioRxiv2023

Executioner caspase is proximal to Fasciclin 3 which facilitates non-lethal activation in Drosophila olfactory receptor neurons

The nervous system undergoes functional modification independent on cell turn over. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins of Drosophila executioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near plasma membrane. We demonstrated that Fas3G-overexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically, Fas3G overexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly-restricted caspase activation, defined by caspase proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase proximal proteins.

molecular biology↗

bioRxiv2023

Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut

BackgroundThe remarkable regenerative abilities observed in planarians and cnidarians are closely linked to the active proliferation of adult stem cells and the precise differentiation of their progeny, both of which typically deteriorate during aging in low regenerative animals. While regeneration-specific genes conserved in highly regenerative organisms may confer regenerative abilities and long-term maintenance of tissue homeostasis, it remains unclear whether introducing these regenerative genes into low regenerative animals can improve their regeneration and aging processes. ResultsHere we ectopically express high regenerative species-specific JmjC domain-encoding genes (HRJDs) in Drosophila, a widely used low regenerative model organism. Surprisingly, HRJD expression impedes tissue regeneration in the developing wing disc but extends organismal lifespan when expressed in the intestinal stem cell lineages of the adult midgut under non-regenerative conditions. Notably, HRJDs enhance the proliferative activity of intestinal stem cells while maintaining their differentiation fidelity, ameliorating age-related decline in gut barrier functions. ConclusionsThese findings together suggest that the introduction of highly regenerative species-specific genes can improve stem cell functions and promote a healthy lifespan when expressed in aging animals.

developmental biology↗

bioRxiv2023

Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth

Post-developmental organ resizing improves organismal fitness under constantly changing nutrient environments. Although stem cell abundance is a fundamental determinant of adaptive resizing, our understanding of its underlying mechanisms remains primarily limited to the regulation of stem cell division. Here we demonstrate that nutrient fluctuation induces dedifferentiation in the Drosophila adult midgut to drive adaptive intestinal growth. From lineage tracing and single-cell RNA-sequencing, we identify a subpopulation of enteroendocrine cells (EEs) that convert into functional intestinal stem cells (ISCs) in response to dietary glucose and amino acids by activating the JAK-STAT pathway. Genetic ablation of EE-derived ISCs severely impairs ISC expansion and midgut growth despite the retention of resident ISCs, and in silico modeling further indicates that EE dedifferentiation enables efficient increase in the midgut cell number while maintaining epithelial cell composition. Our findings uncover a physiologically-induced dedifferentiation that ensures ISC expansion during adaptive organ growth in concert with nutrient conditions.

developmental biology↗