Biology subjects

Yu, G.

Publications and source records attributed to Yu, G..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

F-53B damages cell viability leading to impaired root development in Arabidopsis

The emerging contaminant chlorinated polyfluoroalkyl ether sulfonate (Cl-PFAES/F-53B) has been detected in many plant species, however, the impact of F-53B on the development in plants and the underpinning mechanisms remain largely unelucidated. In this study, we demonstrate by molecular biology, cytogenetics, and fluorescence microscopy mythologies that F-53B impairs cell viability leading to disrupted root development in Arabidopsis (Arabidopsis thaliana). We show that F-53B suppresses root length and the inhibitory effect is pronunanced at increasing concentrations. F-53B disrupts cell wall and microtubule-mediated cell plate formation and configuration in meristem cells, revealing its toxicity to cell division and cytoskeleton organization. F-53B induces cell death predominantly at the meristematic zone, however, gene exression and genetic studies indicate that F-53B does not trigger DNA double-strand breaks, implying a divergent effect on DNA stability across species. Moreover, we show that F-53B damages nuclei stability and viability, and induces Autophagy-Related 8 protein foci formation implying that it triggers autophagy-mediated cell responses. Taken together, this study provides cellular and molecular insights into the toxicity of F-53B to plant cells, which highlights its damage to agriculture and ecology security that deserve imperative environmental management actions. Environmental ImplicationF-53B has been detected in many plant species, which raises increasing concerns on its toxicity to plants and thus agriculture and ecology safety. However, the toxicity of F-53B to development in plants and the underpinning mechanisms remain largely unelucidated. Here, we demonstrate that F-53B damages nuclei stability and viability leading to cell death and impaired root development in the model plant species Arabidopsis thaliana. Our study provides cytogenetic and molecular insights into the F-53B toxicity to plant cells, which highlights imperative environmental management actions and can be referenced for developing F-53B control and management policies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/653422v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@159b211org.highwire.dtl.DTLVardef@1b99a95org.highwire.dtl.DTLVardef@53b964org.highwire.dtl.DTLVardef@b089be_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summaryF-53B triggers DNA double-strand break-free cell unviability leading to impaired meristematic cell division and root development in plants. HIGHLIGHTSO_LIF-53B impairs root development in Arabidopsis. C_LIO_LIF-53B prohibits mitotic cell division at root tips. C_LIO_LIF-53B damages cell viability predominantly at the meristematic zone in seedlings. C_LIO_LIF-53B does not induce DNA double-strand breaks in Arabidopsis seedlings. C_LIO_LIF-53B damages nuclei viability and stability in seedlings. C_LI

developmental biology↗

bioRxiv2025

EasyMultiProfiler: An Efficient Multi-Omics Data Integration and Analysis Workflow for Microbiome Research

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/649266v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@14dd0b1org.highwire.dtl.DTLVardef@1c04a79org.highwire.dtl.DTLVardef@159894dorg.highwire.dtl.DTLVardef@1454a01_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG HighlightsO_LIEasyMultiProfiler provides unified integration of microbial multi-omics data C_LIO_LIEasyMultiProfiler enables natural language-style analytical workflows C_LIO_LIEasyMultiProfiler solves key challenges in standardization and reproducibility C_LIO_LIEasyMultiProfiler extracts meaningful biological insights efficiently C_LI Host-microbiome interactions are crucial in maintaining physiological homeostasis and influencing disease progression. While traditional microbiome research, focused on microbial diversity and abundance, provided essential frameworks, the integration of multi-omics approaches established a far more comprehensive, systems-level understanding of microbiome functionality. However, significant methodological challenges in multi-omics data integration remain, including inconsistent sample coverage, heterogeneous data formats, and complex downstream analytical workflows. These challenges impact the reproducibility and reliability of results and underscore the critical requirement for developing standardized, systematic workflows. Thus, we developed the EasyMultiProfiler (EMP) workflow, a streamlined and efficient analytical framework for multi-omics data analysis. EMP provides a comprehensive infrastructure based on the SummarizedExperiment and MultiAssayExperiment classes, creating a unified framework for storing and analyzing omics data. The frameworks architecture comprises five interconnected functional modules: data extraction, preparation, support, analysis, and visualization. These modules are smoothly integrated into natural language-style analytical workflows, offering users an efficient and standardized solution for multi-omics analysis. EMP addresses critical challenges in multi-omics data analysis, including data integration, workflow standardization, and result reproducibility. The platforms modular architecture and intuitive interface provide researchers and clinicians with a robust, flexible workflow to systematically extract biologically relevant insights from complex multi-omics datasets.

bioinformatics↗

bioRxiv2025

Spatial Transcriptomics Using Archived Formalin-Fixed Paraffin-Embedded Core Needle Biopsy Tissues Revealed Unique Transcriptomic Signatures in Kidney Transplant Rejections

Clinical core needle biopsies present challenges for transcriptomic analysis due to limited tissue volume. In this study, we determined the feasibility of using spatial transcriptomics to evaluate rejection on formalin-fixed paraffin-embedded (FFPE) core needle biopsies from human kidney allografts. We demonstrated that non-rejection, active antibody mediated rejection (AMR), acute cell mediated rejection (TCMR) and chronic active AMR have distinct transcriptomic signatures. Subclusters of monocytes/macrophages with high Fc gamma receptor IIIA (FCGR3A) expression were identified in C4d-positive active AMR and acute TCMR, and the spatial distribution of these cells corresponded to the characteristic histopathological features. Key markers related to monocyte/macrophage activation and innate alloantigen recognition were upregulated, along with metabolic pathways associated with trained immunity in AMR and TCMR. The discovery of unique transcriptomic signatures associated with AMR and TCMR facilitates the differentiation of acute kidney allograft rejections using spatial transcriptomic data derived from FFPE core needle biopsies.

immunology↗

bioRxiv2025

A noncanonical Pol III-dependent, Microprocessor-independent biogenesis pathway generates a germline enriched miRNA family

MicroRNAs (miRNAs) are short RNAs that post-transcriptionally regulate gene expression. In canonical miRNA biogenesis, primary miRNAs are transcribed from intergenic loci or intronic regions by RNA polymerase II, sequentially cleaved by the Microprocessor complex and Dicer, and resulting mature miRNAs are loaded into Argonaute to repress target mRNAs. A minority of miRNAs are generated via noncanonical biogenesis pathways that bypass the Microprocessor and/or Dicer. Here, we describe a new Pol III-dependent, Microprocessor -independent, and Dicer-dependent biogenesis pathway exemplified by the mir-1829 family in C. elegans. Although the mir-1829 family loci reside in intronic regions of protein-coding genes, we show that the miRNAs are derived from independent Pol III transcripts. Unlike other Pol III-dependent miRNAs, the mir-1829 family small RNAs are the dominant species derived from their loci, rather than fragments of a larger functional noncoding RNA. These germline-enriched miRNAs are loaded in multiple miRNA Argonautes, including the recently-characterized germline Argonaute ALG-5, which we demonstrate is repressive when tethered to a reporter transcript. We extend these findings, identifying additional Pol III-transcribed and noncanonical small RNAs in C. elegans and human datasets, including human miR-4521. These young, noncanonical miRNAs may represent an early snapshot in the evolution of de novo miRNA genes.

molecular biology↗

bioRxiv2025

Imputation Disparities Driven by Recent Selectionand Their Impact on Disease Risk Estimation in East and Southeast Asian Populations

Using genotype data consisting of 8,316 individuals, we systematically evaluated imputation performance across six state-of-the-art reference panels for Chinese and Thai populations. A substantial proportion of variants identified through whole-genome sequencing, especially low-frequency variants, remained undetected by existing reference panels. In the Chinese population, the TOPMed panel required an R2 threshold of 0.60-0.70 to achieve comparable imputation accuracy of the ChinaMAP panel without R2 filtering, challenging the standard practice of applying a fixed R2 threshold for downstream analyses. Regional analysis highlighted the role of recent selection in imputation discrepancies and revealed an enrichment of immune-related genes in poorly imputed regions. In addition, we showed that the selection of reference panels and R2 thresholds could significantly influence estimation of polygenic risk score for disease prediction. These findings underscore the importance of developing ancestrally diverse reference panels and provide valuable guidelines for improving genotype imputation in East and Southeast Asian populations.

genomics↗

bioRxiv2025

Epithelial-mesenchymal transition couples with cell cycle arrest at various stages

Numerous computational approaches have been developed to infer cell state transition trajectories from snapshot single-cell data. Most approaches first require projecting high-dimensional data onto a low-dimensional representation; however, this can distort the dynamics of the system. Using epithelial-to-mesenchymal transition (EMT) as a test system, we show that both biology-guided low-dimensional representations and trajectory simulations in high-dimensional state space, not representations obtained with brute force dimensionality-reduction methods, reveal two broad paths of TGF-{beta} induced EMT. The paths arise from the coupling between cell cycle and EMT at either the G1 or G2/M phase, contributing to cell-cycle related EMT heterogeneity. Subsequent multi-plex immunostaining studies confirmed the multiple predicted paths at the protein level. The present study highlights the heterogeneity of EMT paths, emphasizes that caution should be taken when inferring transition dynamics from snapshot single-cell data in two- or three-dimensional representations, and shows that incorporating dynamical information can improve prediction accuracy.

systems biology↗

bioRxiv2025

LivecellX: A Deep-learning-based, Single-Cell Object-Oriented Framework for Quantitative Analysis in Live-Cell Imaging

Live-cell imaging uniquely captures single-cell dynamics in space and time, but robust analysis is limited by segmentation and tracking errors that accumulate across frames. We present LivecellX, a deep-learning-based pipeline that integrates instance-level segmentation error correction with trajectory refinement, leveraging temporal context to recover accurate cell tracks. LivecellX also introduces a benchmark dataset with detailed annotations of common error classes, providing a resource for method development and evaluation. Beyond error correction, the framework incorporates modules for classifying biological processes, reconstructing cell lineages, and analyzing dynamic behaviors. Users can interact with the system programmatically or through a Napari-based graphical interface, enabling flexible integration into diverse workflows. By coupling error-aware correction with comprehensive lineage and dynamics analysis, LivecellX establishes an open, extensible platform that advances the accuracy and scalability of live-cell imaging studies.

biophysics↗

bioRxiv2025

Divergence of Functional Brain Network Configurations in Same and Other Race Face Recognition

The "Other-Race Effect" (ORE) refers to the enhanced memory individuals have for faces within their own racial group compared to other races. This effect is attributed to limited exposure to different races and social-motivational factors affecting face processing. While past research has explored this effect through neuroimaging methods, the precise neural mechanisms that underlie the ORE remain a subject of ongoing investigation. Previous studies have largely adopted a modular perspective, concentrating on the differential activation of face-processing regions when comparing same-race and other-race facial recognition behaviors. However, given the multifaceted nature of the ORE, an exclusive focus on specialized regions may miss the pivotal role played by non-face-preferential brain areas in modulating this phenomenon. In the present study, we take a broader data-driven perspective using graph-theoretical techniques to investigate whole-brain network disparities in same- and other-race facial recognition. Our findings reveal a substantial impact of race on functional connectivity during face memorization. While other-race face recognition benefitted from higher local efficiency during encoding, reduced local efficiency was advantageous for memorization of same-race faces. Notably, successful other-race recognition was disproportionately supported by locally efficient processing in regions among the ventral and dorsal attention networks.

neuroscience↗

bioRxiv2025

ggalign: Bridging the Grammar of Graphics and Biological Multilayered Complexity

Composable visualization is essential in biomedical research, particularly when working with complex, multi-dimensional biological data. However, many existing tools focus on specific fields and lack the comprehensive features needed to capture the intricacies and interrelations of datasets. To address this, we introduce ggalign, an R package built on the grammar of graphics framework, providing an easy-to-use platform for creating composable visualizations of interconnected data. It offers a variety of layout options, including StackLayout, QuadLayout, and CircleLayout, tailored to different data types, and supports flexible multi-dimensional relationships, such as one-to-many, many-to-one, many-to-many, and crosswise connections. Additionally, ggalign enhances the clarity of visualizations through its annotation features. Overall, ggalign offers a powerful and flexible solution for visualizing complex data in biomedical research. O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/636847v1_ufig1.gif" ALT="Figure 1"> View larger version (92K): org.highwire.dtl.DTLVardef@d4bb97org.highwire.dtl.DTLVardef@67c236org.highwire.dtl.DTLVardef@1ff9cc6org.highwire.dtl.DTLVardef@8dc6a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Microglial plasticity governed by state-specific enhancer landscapes

Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging and disease. Whether these microglial subsets represent ontogenically separate lineages of cells, or they are manifestations of plastic changes of microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, to what extent histone modifications and DNA methylation regulate microglial state switches at enhancers have not been defined. Here, using genetic fate mapping, we demonstrate the common embryonic origin of proliferative-region-associated microglia (PAM) enriched in developing white matter, and track their dynamic transitions into disease-associated microglia (DAM) and white matter-associated microglia (WAM) states in disease and aging contexts, respectively. This study links spatiotemporally discrete microglial states through their transcriptomic and epigenomic plasticity, while revealing state-specific histone modification profiles that govern state switches in health and disease.

neuroscience↗

bioRxiv2025

Fenretinide targets GATA1 to induce cytotoxicity in GATA1 positive Acute Erythroid and Acute Megakaryoblastic Leukemic cells.

Patients with Acute Myeloid Leukemia (AML) subtypes, acute erythroleukemia and acute megakaryocytic leukemia (M6 and M7 AMLs, respectively) have a median survival of only a few months with no targeted effective treatment. Our gene expression analysis using the Cancer Cell Line Encyclopedia and CRISPR screen from DepMap showed that M6/M7 AMLs have high levels of the transcription factor GATA1 and depend on GATA1 for survival. While GATA1 was shown to support AML cell proliferation and resistance to chemotherapy, GATA1 has long been considered "undruggable". Here, we identify the small molecule N-(4-hydroxyphenyl)retinamide (4-HPR, Fenretinide) as a novel GATA1 targeting agent in M6 and M7 AML cells, with nM to low M concentrations of 4-HPR causing loss of GATA1. In M6 AML OCIM1 cells, knock-down of GATA1 induced cytotoxicity similarly to low doses 4-HPR while overexpression of GATA1 significantly protected cells from 4-HPR-induced cytotoxicity. In M6 AML cells resistant to current standard-of-care (SOC) Azacytidine plus Venetoclax, 4-HPR synergized with SOC overcoming cell resistance to the drugs. As single-agent, 4-HPR outperformed SOC. In M6 AML cells sensitive to SOC, 4-HPR enhanced and prolonged the growth inhibitory effect of SOC. 4-HPR is a synthetic derivative of vitamin A, and numerous clinical trials have supported its safe profile in cancer patients; therefore, targeted use of 4-HPR against M6 and M7 AMLs may represent a novel therapeutic window. Key Points- Fenretinide (4-HPR) targets the transcription factor GATA1, which was previously thought to be "undruggable" and induces GATA1 loss. - M6 and M7 Acute Myeloid Leukemias (AML) have enriched expression of GATA1 and they can be considered GATA1 positive. - Loss of GATA1 contributes significantly to 4-HPR cytotoxicity in M6 OCIM1 cells. - 4-HPR treatment overcomes chemotherapeutic resistance in M6 Acute Myeloid Leukemia cells, synergizes with standard-of-care and outperforms standard-of-care as a single agent.

cancer biology↗

bioRxiv2025

Regulation of cell cycle by the novel GATA1/TAL1/Sphingomyelin Synthase 1 (SGMS1) transcriptional axis. Implications for anti-leukemic strategies.

Sphingomyelin Synthase 1 (gene name: SGMS1) participates in regulation of sphingolipid levels by synthesizing sphingomyelin from ceramide and phosphatidylcholine. Evidence have supported SGMS1s functions in regulating proliferation, cell cycle, cell death and migration. While its functions have begun to be explored, very little is known about upstream regulators. Here, we demonstrate that SGMS1 is a direct gene target of the GATA1-TAL1 transcriptional complex in K562 erythroleukemic cells. A predicted GATA1 consensus DNA binding sequence was identified with in a newly characterized alternative SGMS1 promoter (TSS-7 promoter) and ChIP analysis confirmed GATA1 occupancy on the promoter. Down-regulation of GATA1 in K562 cells significantly decreased SGMS1 expression and enzymatic activity, and ChIP-Seq analysis from ENCODE showed colocalized peaks for GATA1 and TAL1 (a well-established GATA1 DNA binding partner) on the SGMS1 gene. Analysis of publicly available datasets shows that elevated GATA1, TAL1 and SGMS1 expression not only clusters GATA1 positive chronic myelogenous leukemia cells (like K562), but also selectively identifies acute erythrocytic and megakaryocytic leukemias (M6 and M7 AML, respectively). Microarray gene expression analysis after down-regulation of SGMS1 in M6 AML Hel cells revealed alteration of genes regulating G2/M check point and mitotic spindle formation. This phenotype was functionally confirmed by the significant delay in G2/M cell cycle progression of cells with SGMS1 downregulation and sensitization to the clinically relevant anti-mitotic agent, Taxol. Altogether, these results identify SGMS1 as a novel target of GATA1/TAL1 transcriptional complex and they support a role for the GATA1/TAL1/SGMS1 axis in regulating transit through G2/M. Importantly, results also point to combination of anti-mitotic agents and inhibition of SGMS1 as a potential novel therapeutic approach against the aggressive and resilient M6 AMLs. KEY POINTSO_LIThe Sphingomyelin Synthase 1 gene (SGMS1) is a novel direct target of GATA1 and TAL1. C_LIO_LIHigh SGMS1 levels are associated with high GATA1/TAL1 expression and regulate cell cycle progression through the G2/M checkpoint in GATA1+ erythroleukemic Acute Myeloid Leukemia Hel cells. C_LIO_LIHigh SGMS1 is associated with lower probability of survival of patients with Acute Myeloid Leukemia and down-regulation of SGMS1 co-operates with microtubule targeting agents to induce cytotoxicity in GATA1 positive AML Hel cells. C_LI

cancer biology↗

bioRxiv2025

The Ralstonia solanacearum effector RipAV targets Plant U-box proteins and induces proteasomal-dependent degradation of BIK1

Plants have developed a complex immune system to detect and respond to invading pathogens. A critical aspect of this defence relies on regulatory mechanisms that control the activation of immune responses, ensuring these are efficient yet do not compromise overall plant performance. Many pathogens secrete proteins called effectors to manipulate plant cellular functions, suppressing plant immunity and promoting infection. Here, we show that the bacterial effector RipAV, secreted by the soil-borne bacterial pathogen Ralstonia solanacearum, hijacks a major immune signalling hub to suppress immune responses. RipAV targets members of the plant-specific ubiquitin ligase (PUB) family and calcium-dependent protein kinase 28 (CPK28), which has been shown to phosphorylate a set of PUBs to enhance their activity and regulate the stability of the key immune regulator BIK1. RipAV association enhances the CPK28-mediated phosphorylation of PUBs, inducing the proteasome-mediated degradation of BIK1 and the suppression of immunity. Importantly, we found that RipAV is required for maintaining a low accumulation of BIK1 during a R. solanacearum infection. These findings provide new insights into the sophisticated strategies employed by pathogens to subvert plant immunity.

plant biology↗

bioRxiv2025

Mesoscale landscaping of the TRIM protein family reveals a novel human condensatopathy

The mesoscale organization of cells is central to cellular physiology and pathology. Cellular condensates often form via biomolecular phase separation, mediated by intrinsically disordered regions (IDRs) and represent a key mechanism for mesoscale organization. The TRI-partite Motif (TRIM) family of ubiquitin ligases is implicated in diverse cellular functions and disease, yet the role of biomolecular condensation in TRIM family organization remains understudied. Here, we systematically investigate the mesoscale localization of 72 TRIM proteins, revealing that a majority form condensates in distinct cellular compartments. IDR content correlates with dynamic condensate formation, suggesting a critical role in mesoscale organization. Focusing on TRIM8, associated with a neuro-renal disorder, we demonstrate that disease-causing truncations of the TRIM8 C-terminal IDR result in a condensatopathy, characterized by disrupted condensation, proteasomal regulation, and TAK1/NF{kappa}B signaling. Functional assays in cellular and animal models link these disruptions to podocyte dysfunction and impaired response to injury. Our findings establish a framework for understanding condensatopathies and the mesoscale principles governing TRIM family organization and function.

cell biology↗

bioRxiv2024

Genetically Labeled Premyelinating Oligodendrocytes: Bridging Oligodendrogenesis and Neuronal Activity

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied. Here, we generated a knock-in mouse line that specifically labels preOLs across the central nervous system. Genetically labeled preOLs exhibit distinct morphology, unique transcriptomic and electrophysiological features, and do not overlap with OPCs. PreOL lineage tracing revealed that subsets of them undergo prolonged maturation and that different brain regions initiate oligodendrogenesis with the spatiotemporal specificity. Lastly, by fate mapping preOLs under sensory deprivation, we find that neuronal activity functions within a narrow time window of preOL maturation to promote their survival and successful integration. Our work provides a new tool to probe this critical cell stage during axon ensheathment, allowing for fine dissection of axon-oligodendrocyte interactions.

neuroscience↗

bioRxiv2024

The Landscape of Sex- and APOE Genotype-Specific Transcriptional Changes in Alzheimer's Disease at the Single Cell Level

Alzheimers disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients are females. Basic and clinical research studies show evidence supporting sex-specific differences contributing to the complexity of AD. There is also strong evidence supporting sex-specific interaction between the primary genetic risk factor of AD, APOE4 and AD-associated neurodegenerative processes. Recent studies by us and others have identified sex and/or APOE4 specific differentially expressed genes in AD based on the bulk tissue RNA-sequencing data of postmortem human brain samples in AD. However, there lacks a comprehensive investigation of the interplay between sex and APOE genotypes at the single cell level. In the current study, we systematically explore sex and APOE genotype differences in single cell transcriptomics in AD. Our work provides a comprehensive overview of sex and APOE genotype-specific transcriptomic changes across 54 high-resolution cell types in AD and highlights individual genes and brain cell types that show significant differences between sexes and APOE genotypes. This study lays the groundwork for exploring the complex molecular mechanisms of AD and will inform the development of effective sex- and APOE-stratified interventions for AD.

genomics↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗

bioRxiv2024

Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex

Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, Dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein Connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondria dynamics as a critical step in neurodevelopment. SummaryDuring cortical astrocyte morphogenesis, mitochondria fragment and decrease in size to populate distal astrocyte processes. Drp1-mediated mitochondrial fission is necessary for peripheral astrocyte process formation. Astrocyte-specific Drp1 loss induces astrocyte reactivity, disrupts cortical astrocyte organization, and dysregulates PAP proteins including gap-junction protein Connexin 43 abundance.

cell biology↗