Biology subjects

Hagiwara, A.

Publications and source records attributed to Hagiwara, A..

4 recordsLinked to original sources

bioRxiv2026

PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity

PLCXD proteins have been linked to phosphoinositide metabolism for more than a decade, and PLCXD2 activity has been associated with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] depletion, yet its preferred direct substrate has remained unresolved. Here, cellular lipidomics showed that catalytically active PLCXD2 reduced the major phosphatidylinositol (PI) 38:4 species, with more modest phosphoinositide changes and increased diacylglycerol (DAG) and phosphatidic acid (PA). Using recombinant PLCXD2 and acyl-chain-matched substrates, we found that PLCXD2 hydrolyzed PI substantially more efficiently than PI(4,5)P2 and most other phosphoinositides tested. In Plcxd2-deficient retina, PI abundance was preserved, whereas DAG and PA were reduced without broad changes in major membrane phospholipid classes. PLCXD2 loss was associated with early structural abnormalities at the photoreceptor-bipolar synaptic interface, followed by outer nuclear layer thinning and reduced electroretinographic a-wave responses. These findings identify PLCXD2 as a PI-preferring mammalian PLC and reveal an endogenous role in retinal lipid homeostasis and outer retinal integrity.

biochemistry↗

bioRxiv2024

Body size interacts with the structure of the central nervous system: A multi-center in vivo neuroimaging study

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subjects sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1{+/-}6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44[≤]r[≤]0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21[≥]r[≥]-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20[≥]r[≥]-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39[≤]r[≤]0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22[≥]r[≥]-0.25). Linear mixture of sex and age explained 26{+/-}10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33{+/-}11% when body height was added into the mixture model. Age itself explained only 2{+/-}2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.

neuroscience↗

bioRxiv2022

Single-cell analysis characterizes non-enhancing region of recurrent high-grade glioma

BackgroundNon-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. MethodsWe leveraged single-nucleus RNA-sequencing on 15 specimens from 5 high grade gliomas to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining for Ki67 to identify proliferative cell burden. ResultsTumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched for mesenchymal-like states. These NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and presence of cell-mediated immune response, but increased glioma-to-non-pathological cellular interactions. ConclusionsThis comprehensive analysis illustrates differing tumor and non-tumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. Key PointsSignificant proliferating tumor burden exist in non-enhancing regions of glioma; non-enhancing regions have unique tumor and non-tumor expression properties Importance of StudyStandard of care treatment for glioblastoma relies on visualization of tumor via contrast-enhanced magnetic resonance imaging. However, non-enhancing regions harbor tumor cells that should be targets for adjuvant therapy given these regions are not resected in surgery. To begin addressing these infiltrating non-enhancing tumor cells, we thoroughly characterize the tumor and non-tumor microenvironment of non-enhancing regions in high grade gliomas. Understanding the total tumor burden, proliferating tumor ratio, and presence of putative glioma stem cells may help design adjuvant therapies for these unique population of tumor cells. Understanding the non-tumor immune and vascular microenvironment may help target these areas in regards to drug delivery and immunotherapy. Overall, in a disease marked by significant intratumoral heterogeneity, we focus identifying therapeutic strategies for areas not addressed at surgery.

neuroscience↗

bioRxiv2020

Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis

Mechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress during muscle formation remain unclear. Here, we investigate the role of the mechano-sensitive ion channel Piezo1 during myogenic progression. Direct manipulation of Piezo1 in muscle stem cells alters their myogenic progression. Indeed, Piezo1 knockdown suppresses myoblast fusion leading to smaller myotubes. Such event is accompanied by significant downregulation of the fusogenic protein Myomaker. In parallel, while Piezo1 knockdown also lowers Ca2+ influx in response to stretch, Piezo1 activation increases Ca2+ influx in response to stretch and enhances myoblasts fusion. We believe these findings may help understand molecular defects present in some muscle diseases. Altogether our study shows that Piezo1 is essential for terminal muscle differentiation acting on myoblast fusion, suggesting that Piezo1 deregulation may have implications in muscle aging and degenerative diseases including muscular dystrophies.

molecular biology↗