Biology subjects

Park, J.-S.

Publications and source records attributed to Park, J.-S..

At least 19 recordsLinked to original sources

bioRxiv2026

HNF4A maintains proximal tubule identity and limits injury-associated cell states in the adult mouse kidney

Introduction: HNF4A is required for proximal tubule maturation during kidney development, but its role in maintaining proximal tubule identity in the adult kidney has not been defined. Following acute kidney injury, Hnf4a expression is rapidly suppressed in proximal tubule cells, coinciding with loss of mature epithelial features and activation of injury-associated transcriptional programs. It remains unknown whether HNF4A loss is sufficient to drive injury-associated transcriptional changes. Methods: We conditionally deleted Hnf4a in mature proximal tubules using Slc34a1Cre in mice and analyzed the consequences of Hnf4a loss in adult kidneys. To identify genes directly regulated by HNF4A, we performed proximal tubule-specific transcriptional profiling together with genome-wide mapping of HNF4A binding sites using CUT&RUN. Results: In Hnf4a mutant kidneys, HNF4A protein initially persisted in proximal tubules but was progressively lost from convoluted proximal tubule cells. Loss of Hnf4a resulted in downregulation of proximal tubule-specific transport and metabolic genes, accompanied by reactivation of developmental and injury-associated genes. CUT&RUN analysis revealed that HNF4A directly regulates genes predominantly involved in solute transport and metabolic processes. Conclusions: These findings identify HNF4A as a key regulator of proximal tubule identity and homeostasis in the adult mouse kidney. Genetic loss of Hnf4a in mature proximal tubules leads to loss of mature proximal tubule gene expression and activation of injury-associated transcriptional programs, implicating Hnf4a suppression as a potential contributor to maladaptive repair after kidney injury.

developmental biology↗

bioRxiv2026

Loss of Hnf1b in differentiated proximal tubule cells uncovers nephron segment plasticity

HNF1B is a transcription factor required for proximal tubule (PT) specification during kidney development, but whether it is also required to maintain PT identity after differentiation remains unknown. Using PT-specific genetic deletion in mice, we found that loss of Hnf1b in differentiated PT cells causes cyst formation and early postnatal lethality. PT-specific transcriptomic analysis revealed downregulation of PT-specific gene programs, including Hnf4a and PT-enriched transport and metabolic genes. Strikingly, Hnf1b-deficient PT cells ectopically activated podocyte-specific genes, including Wt1 and Nphs1, demonstrating that PT cells retain the capacity to engage alternative nephron segment programs when identity-stabilizing mechanisms are disrupted. In addition, loss of Hnf1b disrupted epithelial integrity, as evidenced by reduced epithelial adhesion gene expression and induction of mesenchymal markers. Wnt/{beta}-catenin signaling was also aberrantly activated, suggesting broader dysregulation of epithelial homeostasis. These findings establish HNF1B as a critical post-specification regulator of PT identity that sustains PT-specific transcriptional programs and actively suppresses alternative segmental identity programs.

developmental biology↗

bioRxiv2026

EES-Transformer: A Dual-Path Transformer for Tissue Classification and Gene Representation Learning from Extreme Expression Sets

Accurate tissue classification from gene expression data is fundamental to transcriptomic analysis. Here we introduce EES-Transformer V2, a dual-path transformer architecture that learns from Extreme Expression Sets (EES)--sequences of genes at expression extremes (above 95th or below 5th percentile). The architecture separates tissue classification from masked language modeling through independent branches: the classification branch operates without tissue label information, while the generative branch receives tissue conditioning. This design enables fair evaluation of classification performance while learning tissue-specific gene relationships. Applied to 12,212 Arabidopsis thaliana RNA-seq samples spanning 47 tissue types, EES-Transformer achieves 91-92% classification accuracy (varying across evaluation runs due to stochastic input masking)--substantially above the 2.1% random baseline. Attention-based analysis identifies 3,524 gene-tissue high-attention associations whose importance patterns reflect known biology. Critically, while individual high-attention genes appear broadly across tissues, gene pairs from attention-derived regulatory networks show higher tissue specificity: pollen gene pairs show a 2.7-fold enrichment over single-gene rates, and root and leaf pairs each show 1.5-fold enrichment. This finding reveals that tissue identity is encoded in combinatorial gene expression patterns rather than individual genes. Attention-derived gene regulatory networks exhibit scale-free topology and biologically coherent hub gene programs, with pollen networks consisting entirely of DOWN-DOWN interactions among silenced vegetative genes. EES-Transformer provides accurate tissue classification, interpretable gene importance scores, and attention-derived regulatory networks for biological discovery.

bioinformatics↗

bioRxiv2026

GeneReL: A Large Language Model-Powered Platform for Gene Regulatory Relationship Extraction with Community Curation

MotivationGene regulatory networks provide fundamental insights into plant biology, yet extracting structured interaction data from scientific literature remains a significant bottleneck. Traditional manual curation cannot scale to meet the demands of modern research, while automated text mining approaches struggle with the complexity of gene nomenclature and relationship classification. Large language models offer promising capabilities for information extraction, but integrated platforms combining LLM extraction with community validation for plant regulatory databases remain scarce. ResultsWe developed GeneReL, an integrated platform combining LLM-based extraction with community-driven curation for gene regulatory networks in Arabidopsis thaliana. The system employs a tiered pipeline using Claude Haiku 4.5 for screening, Claude Sonnet 4 for extraction, and Claude Opus 4 for verification, along with a novel five-step gene normalization pipeline incorporating paper-text search and LLM-based disambiguation with UniProt annotations. The database contains 13,710 curated interactions across 51 relationship types, with 90.2% classified as high confidence based on linguistic certainty markers in source text. Comparison with IntAct reveals 86.8% of interactions are unique to our literature-derived database, demonstrating complementary coverage to existing resources. The web platform provides card-based browsing with voting capabilities, interactive network visualization using Cytoscape.js with locus-ID-based node consolidation, and administrative interfaces for curator review of ambiguous gene mappings. Availability and ImplementationGeneReL is freely accessible at https://generel.newgenes.me. Contactkangyangjae@gnu.ac.kr

bioinformatics↗

bioRxiv2026

A knock-in Six2Cre line reveals transient interstitial potential in nephron progenitors

The developmental relationship between nephron progenitors and the renal interstitium remains unresolved, in part due to limitations of existing lineage tracing tools. The widely used transgenic Six2TGC line, which is routinely employed to target the nephron lineage, exhibits mosaic recombination and altered progenitor dynamics. To overcome these shortcomings, we generate a knock-in Six2Cre mouse allele that faithfully recapitulates endogenous Six2 expression, preserves nephron endowment, and achieves near-complete, non-mosaic recombination. Side-by-side lineage tracing with Six2Cre and Six2TGC, combined with RNA velocity analysis of single-cell RNA-sequencing datasets, reveals a brief interval around embryonic day 11 during which Six2-expressing mesenchymal nephron progenitors contribute to the renal interstitium. This contribution is transient and stage-restricted. These findings reveal an early dual potential within nephron progenitors and define a precise developmental window for dissecting mechanisms that coordinate nephron-interstitium integration.

developmental biology↗

bioRxiv2025

Constitutive Yap activation in distal nephron segments disrupts epithelial identity and nephron patterning

The distal nephron segments play a critical role in maintaining electrolyte balance, yet the mechanisms that preserve epithelial identity and segmental organization within this region remain poorly defined. Yes-associated protein (Yap), a key effector of Hippo signaling, is essential for kidney development, but its function in distal nephron epithelia is unknown. Using a genetic gain-of-function approach to activate Yap selectively in distal nephron segments, we found that sustained Yap activity profoundly disrupts epithelial organization and nephron patterning. Lineage tracing revealed that both distal convoluted tubule and connecting tubule cells originate from Slc12a3-expressing cells, and Yap activation in these segments led to increased proliferation, displacement of lineage-labeled cells beyond expected segment boundaries, and loss of segment-specific gene expression. These changes were accompanied by defects in apicobasal polarity and junctional integrity, consistent with epithelial plasticity. Unexpectedly, Yap activation in distal nephron segments also suppressed proximal tubule gene expression, indicating non-cell-autonomous effects on nephron differentiation. Together, these findings identify Yap as a critical regulator of epithelial identity in the distal nephron segments and reveal a previously unrecognized role for Hippo signaling in coordinating intersegmental organization during kidney development.

developmental biology↗

bioRxiv2025

T-Cell Synaptosomes Orchestrate Long-Term Anti-Tumor Immunity via Proliferative and Metabolic Reprogramming

A defining feature of T-cell activation is its dependence on physical contact with antigen-presenting cells (APCs). During this interaction, activated T cells release microvesicles, known as T-cell immunological synaptosomes (TIS), onto the surface of APCs. While TIS are known to activate APCs, their broader in vivo functions remain largely unexplored. Here, we show that TIS are primarily phagocytosed by macrophages and dendritic cells, persist intracellularly for several days, and reprogram these cells in a manner distinct from LPS. TIS upregulate genes involved in metabolism, proliferation, and anti-inflammatory responses, and promote immune cell recruitment, including eosinophils. Notably, TIS induce minimal immune activation upon initial exposure but trigger a rapid and robust response upon secondary administration, indicating a priming effect reminiscent of adaptive immunity. In an MC38 colon cancer model, TIS treatment resulted in near-complete tumor suppression and durable protection upon rechallenge, highlighting their potential as a potent and long-lasting immunotherapeutic platform.

immunology↗

bioRxiv2025

Characterization of zebrafish nucleus pulposus in development and aging: A fish model for probing human intervertebral disc degeneration and regeneration

Intervertebral disc (IVD) degeneration (IDD) contributes to low back and neck pain. The nucleus pulposus (NP) of the IVD is usually degenerated first in age-related IDD. Addressing NP degeneration remains challenging due to insufficient understanding of its etiologies. Here, we characterize zebrafish IVD, particularly the NP, and note several characteristics that are common to or different from those of mammals. The adult zebrafish NP can be partitioned into three sections: the NP envelope with a monolayer of basal cells, the peripheral region with clustered vacuolated and non-vacuolated NP cells, and the central fibrotic region with low cellularity. With age, the percentage of vacuolated NP cells decreases, whereas that of non-vacuolated NP cells increases, as in mammals. However, a cluster of vacuolated cells persists in the NP periphery even in aged zebrafish. Notably, the ratio of the span of the fibrotic NP center to NP diameter remains largely constant at 50% regardless of age, suggesting that the zebrafish NP can better maintain its overall shape and structure, compared to mammalian NP. The fibrotic NP center and cell-populated NP periphery serve as internal controls to each other for studying NP maintenance and fibrosis. With external development, high fecundity, and great regenerative capabilities, zebrafish may be a unique NP model to complement mammalian models for studying how the NP degenerates and how the dormant capability of NP regeneration may be revitalized in humans.

developmental biology↗

bioRxiv2025

Nanoscopy of Organelle Handoff Portals Reveals Direct Coupling between ER Remodeling and Microtubule-Based Transport

How biosynthetic organelles leave the endoplasmic reticulum (ER) and engage with microtubule tracks remains a central question. Combining interferometric scattering with fluorescence nanoscopy, we tracked nanometer-scale handoff events in living cells. ER-derived organelles undergo biased diffusion along ER tubules toward nearby microtubules. ER three-way junctions function as nanoscopic hubs where cargo pauses, contacts multiple microtubules, and then launches onto a track for long-range travel. Remarkably, the ER maintains a membrane tether to the departing cargo, extending its tubules and forming new junctions, thereby coupling inter-network transfer with membrane morphogenesis. These observations reveal an integrated mechanism that links organelle biogenesis, directional trafficking, and continual ER- and cellular remodeling, underscoring the ERs active role in steering transport and repurposing its own output within the crowded intracellular environment.

cell biology↗

bioRxiv2025

Single-Cell Spatial Mapping of Human Kidney Development Reveals the Critical Role of the Local Microenvironment in Cell Fate Decisions

Cell-cell interactions play a pivotal role in organ development, yet these communications have previously been studied one interaction at a time in model organisms, leaving a gap in our understanding of the cellular interplay in human development. To address this, we investigated human kidney development using single-cell RNA sequencing and spatial transcriptomics, analyzing over 500,000 cells. By mapping gene expression and differentiation trajectories in histologic space, we define the spatial organization of kidney development. Our analysis revealed newfound plasticity, showing that nephron progenitor cells undergo an early fate decision between renal corpuscle and tubular lineages. However, this choice is later reversed with some mature tubule cells transitioning back to a renal corpuscle fate. Further, through a genome-wide, spatially-aware cell-cell interaction analysis, we identified specific ligands and neighboring cell signals that create biologically meaningful cellular neighborhoods and mediate cell fate choices, offering a blueprint to understand the coordination of human development at scale.

genomics↗

bioRxiv2025

The thin descending limb of the loop of Henle originates from proximal tubule cells during mouse kidney development

BackgroundThe thin descending limb of the loop of Henle is crucial for urine concentration, as it facilitates passive water reabsorption. Despite its importance, little is known about how this nephron segment forms during kidney development. MethodsWe assembled a large single-cell RNA sequencing (scRNA-seq) dataset by integrating multiple datasets of non-mutant developing mouse kidneys to identify developing thin descending limb cells. To test whether those cells originate from proximal tubule cells, we generated a proximal tubule-specific Cre line, Slc34a1eGFPCre, and conducted lineage tracing. Additionally, given that the transcription factor Hnf4a directly binds to the Aqp1 gene, we examined whether the loss of Hnf4a affects Aqp1 expression in thin descending limb cells. ResultsFrom our scRNA-seq dataset, we identified a small cluster of cells distinct from both the proximal tubule and the thick ascending limb of the loop of Henle. Those cells exhibited high expression of thin descending limb marker genes, including Aqp1 and Bst1. Notably, a subset of proximal tubule cells also expressed thin descending limb marker genes, suggesting that proximal tubule cells may give rise to thin descending limb cells. Using lineage tracing with the Slc34a1eGFPCre line, we found that, at least, a subset of thin descending limb cells are descendants of proximal tubule cells. Furthermore, the loss of Hnf4a, a transcription factor essential for mature proximal tubule cell formation, disrupted proper Aqp1 expression in thin descending limb cells, providing additional evidence of a developmental link between proximal tubule cells and thin descending limb cells. ConclusionOur findings shed new light on the developmental origin of thin descending limb cells and highlight the importance of Hnf4a in regulating their formation. Key PointsO_LIReference single cell RNA-seq dataset of the developing mouse kidney was assembled and used to identify the thin descending limb of the loop of Henle. C_LIO_LILineage analysis of proximal tubules in the mouse kidney shows that proximal tubule cells give rise to the thin descending limb of the loop of Henle. C_LIO_LIDeletion of Hnf4a disrupts the expression of Aqp1 in the thin descending limb of the loop of Henle, highlighting a developmental link between proximal tubules and the loop of Henle. C_LI

developmental biology↗

bioRxiv2024

The Transcription Factor TCF21 is necessary for adoption of cell fates by Foxd1+ stromal progenitors during kidney development.

Normal kidney development requires the coordinated interactions between multiple progenitor cell lineages. Among these, Foxd1+ stromal progenitors are essential for nephrogenesis, giving rise to diverse cell types including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms governing their differentiation remain poorly understood. This study investigates the role of Tcf21, a mesoderm-specific bHLH transcription factor, in Foxd1+ cell fate determination. Using single-cell RNA sequencing (scRNA-seq), we analyzed 32,461 GFP+ cells from embryonic day 14.5 (E14.5) Foxd1Cre/+;Rosa26mTmG;Tcf21f/fkidneys (Tcf21-cKO) and controls. Clustering identified a predominant stromal population, further divided into six subpopulations associated with healthy kidney development: nephrogenic zone-associated stroma, proliferating stroma, medullary/perivascular stroma, collecting duct-associated stroma, differentiating stroma, and ureteric stroma. Loss of Tcf21 resulted in marked depletion of medullary/perivascular stroma, collecting duct-associated stroma, proliferating stroma, and nephrogenic zone-associated stroma stromal subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces. Additionally, we identified a novel cluster unique to Tcf21-cKO kidneys, characterized by high expression of Endomucin (Emcn), a vascular endothelial marker. These cells spanned across pseudotime trajectories and were distributed broadly across the mutant kidney. The emergence of Emcn-expressing cells in Tcf21-cKO kidneys coincided with a reduction in Acta2-expressing medullary stromal cells, suggesting a population shift. Our findings highlight the critical role of Tcf21 in directing Foxd1+ progenitor differentiation. Loss of Tcf21 disrupts stromal cell fates, leading to aberrant kidney development and providing new insights into the mechanisms underlying congenital kidney anomalies. TRANSLATIONAL STATEMENTThis study reveals critical insights into kidney development and congenital anomalies by identifying the developmental origins of stromal heterogeneity and the key role of Tcf21 in stromal progenitor differentiation. These findings enhance our understanding of stromal cell fate decisions and their relevance to congenital disorders. Additionally, this work provides valuable information for improving the recapitulation of the stromal compartment ex vivo, a current challenge in kidney organoid models. The role of Tcf21 in stromal phenotypic modulation underscores its broader significance in tissue repair and fibrotic diseases, suggesting potential avenues for therapeutic intervention.

developmental biology↗

bioRxiv2024

Determination of the absolute concentration of Rayleigh particles via scattering microscopy

Nanoparticles are crucial in diverse fields such as healthcare, electronics, and energy. Their small size allows them to cross biological barriers, enhancing drug delivery but also posing health risks. Accurate characterization of nanoparticles is essential for assessing their safety and efficacy, particularly in medical applications. Traditional methods such as dynamic light scattering and mass spectrometry have limitations in sensitivity and range of application. To address these challenges, we introduce the interferometric Concentration Analyzer and Ultrasmall Nanoparticle Tracker (iCAUNT), a technique for detecting and quantifying nanoparticles smaller than one-tenth of the imaging light wavelength. As a non-invasive method, iCAUNT provides precise size and concentration measurements of biological and synthetic nanoparticles, offering significant potential for diagnostics, therapeutics, and broader nanoscience applications.

biophysics↗

bioRxiv2023

Intermolecular interactions between cysteine and aromatic amino acids with phenyl moiety in the DNA-binding domain of heat shock factor 1 regulate thermal stress-induced trimerization.

In this study, we investigated the trimerization mechanism and structure of heat shock factor 1 (HSF1) in humans, goldfish, and walleye pollock at various temperatures. The trimerization of HSF1s were confirmed using western blotting using their respective antibodies. First, we examined the HSF1 DNA-binding domains of human (Homo sapiens), goldfish (Carassius auratus), and walleye pollock (Gadus chalcogrammus) by mutating key residues (36 and 103) that are thought to directly affect trimer generation. Humans, goldfish, and walleye pollock contain cysteine at residue 36, but cysteine (C), tyrosine (Y), and phenylalanine (F) at residue 103. Also, the trimer formation temperature of each species was found to be 42, 37, and 20 {degrees}C, respectively. In the mutation experiment, trimerization formed at 42 {degrees}C when residue 103 was C, at 37 {degrees}C it was Y, and at 20 {degrees}C it was F, regardless of the species. In addition, it was confirmed that when residue 103 of the three species was mutated to alanine (A), trimer was not formed. This suggest that, in addition to the previously identified C-C disulfide bonds in humans, C forms a trimer with a new type of bond with aromatic ring residues such as Y and F. Thus, HSF1 trimer formation temperature reveals the trimer creation mechanism through the fact that goldfish can have C-Y bonds at 37 {degrees}C, and walleye pollock can have C-F bonds at 20 {degrees}C. This study suggests that the trimer formation temperature and mechanism of HSF1 are regulated by the amino acid at residue 103.

biochemistry↗

bioRxiv2023

Hedgehog signaling is required for the maintenance of mesenchymal nephron progenitors

Mesenchymal nephron progenitors (mNPs) give rise to all nephron tubules in the mammalian kidney. Since premature depletion of these cells leads to low nephron numbers, high blood pressure, and various renal diseases, it is critical that we understand how mNPs are maintained. While Fgf, Bmp, and Wnt signaling pathways are known to be required for the maintenance of these cells, it is unclear if any other signaling pathways also play roles. In this report, we explored the role of Hedgehog signaling in mNPs. We found that loss of either Shh in the collecting duct or Smo from the nephron lineage resulted in premature depletion of mNPs. Transcriptional profiling of mNPs with different Smo dosages suggested that Hedgehog signaling inhibited Notch signaling and upregulated the expression of Fox transcription factors such as Foxc1 and Foxp4. Consistent with these observations, we found that ectopic expression of Jag1 caused the premature depletion of mNPs as seen in the Smo mutant kidney. We also found that Foxc1 was capable of binding to mitotic condensed chromatin, a feature of a mitotic bookmarking factor. Our study demonstrates a previously unappreciated role of Hedgehog signaling in preventing premature depletion of mNPs by repressing Notch signaling and likely by activating the expression of Fox factors. TRANSLATIONAL STATEMENTPremature depletion of nephron progenitors results in low nephron endowment, leading to high blood pressure and various renal diseases. Sound understanding of the molecular mechanisms underlying the maintenance of nephron progenitors is required for intervention. Although defective Hedgehog signaling is known to cause Pallister-Hall syndrome, its activity in nephron progenitors has been elusive. Here we report that Hedgehog signaling plays an important role in maintaining nephron progenitors. Our findings suggest that Hedgehog signaling pathway is a potential target for enhancing nephron endowment.

developmental biology↗

bioRxiv2023

Shear-induced phenotypic transformation of microglia in vitro

Brain cells are influenced by continuous fluid shear stress driven by varying hydrostatic and osmotic pressure conditions, depending on the brains pathophysiological conditions. While all brain cells are sensitive to the subtle changes in various physicochemical factors in the microenvironment, microglia, the resident brain immune cells, exhibit the most dramatic morphodynamic transformation. However, little is known about the phenotypic alterations in microglia in response to the changes in fluid shear stress. In this study, we first established a flow-controlled microenvironment to investigate the effects of shear flow on microglial phenotypes, including morphology, motility, and activation states. Microglia exhibited two distinct morphologies with different migratory phenotypes in a static condition: bipolar cells that oscillate along their long axis and unipolar cells that migrate persistently. When exposed to flow, a significant fraction of bipolar cells showed unstable oscillation with an increased amplitude of oscillation and a decreased frequency, which consequently led to the phenotypic transformation of oscillating cells into migrating cells. Interestingly, the level of pro-inflammatory genes increased in response to shear stress, while there were no significant changes in the level of anti-inflammatory genes. Our findings suggest that an interstitial fluid-level stimulus can cause a dramatic phenotypic shift in microglia toward pro-inflammatory states, shedding light on pathological outbreaks of severe brain diseases. Given that the fluidic environment in the brain can be locally disrupted in pathological circumstances, the mechanical stimulus by a fluid flow should also be considered a crucial element in regulating the immune activities of the microglia in brain diseases. Statement of SignificanceCellular morphology and motility are important factors that encompass the alterations in protein and gene-level expressions within cells. In pathological conditions, microglia, the resident brain immune cells, are known to undergo morphodynamic transformations in response to various physicochemical stimuli. Besides the commonly known soluble biochemical factors in the microenvironment, the differential flow characteristics of ISF have been linked to several neurological diseases, such as Alzheimers, Parkinsons, and brain tumors. Microglial cells, which are extremely sensitive to subtle changes in extracellular stimuli, have been identified as key players in these pathological conditions. Despite its importance, however, it has been challenging to study the sole effect of a shear flow on microglia. We investigated the morphodynamic features of microglia in response to precisely controlled interstitial-level fluid flow conditions using a microfluidic system in which isolated microglia are monitored in real-time while the undesirable effects from other extracellular factors are minimized.

bioengineering↗

bioRxiv2022

Interstitial Notch signaling regulates nephron development via the Gata3-Renin axis in the mouse kidney

Notch signaling in the renal interstitium is known to be required for the formation of mesangial cells and Ren1 (Renin)-expressing cells. However, little is known about how interstitial Notch signaling affects nephron development. We found that blocking Notch signaling in the renal interstitium in mice caused developmental arrest of proximal tubules accompanied by defective formation of mesangial cells. We examined the interstitial Pdgfrb mutant kidney which exhibits a similar mesangial cell defect and found that the Pdgfrb mutant kidney showed normal proximal tubule development, suggesting that the absence of mesangial cells was not the cause of defective proximal tubule development. Our single cell RNA-seq analysis of the interstitial Rbpj mutant kidney showed that a subset of proximal tubule genes were downregulated in the mutant kidney and that Gata3 was downregulated in the mutant interstitium during the development of Ren1-expressing cells. We found that deleting Gata3 in the interstitium caused the loss of Renin and the developmental arrest of proximal tubules, phenocopying the interstitial Notch/Rbpj mutants. Our results suggest that interstitial Notch signaling regulates the development of proximal tubules via the Gata3-Renin axis in the mouse kidney.

developmental biology↗

bioRxiv2022

Interaction between VPS13A and the XK scramblase is required to prevent VPS13A disease in humans

VPS13 family proteins form conduits between the membranes of different organelles through which lipids are transferred. In humans there are four VPS13 paralogs each of which is required to prevent a different inherited disorder. VPS13 proteins contain multiple conserved domains. The VAB domain binds to adaptor proteins to recruit VPS13 to specific membrane contact sites. This work demonstrates the importance of a different domain in VPS13A in preventing VPS13A disease (chorea-acanthocytosis). The Pleckstrin Homology (PH) domain at the C-terminus of VPS13A is required to form a complex with the XK scramblase and for proper localization of VPS13A within the cell. Mutations in the interaction surface between VPS13A and XK predicted by Alphafold modeling disrupt complex formation and colocalization of the two proteins. Mutant VPS13A alleles found in patients with VPS13A disease truncate the PH domain. The phenotypic similarities between VPS13A disease and McLeod syndrome caused by mutations in XK argue that loss of VPS13A-XK complex is the basis of both diseases. Summary StatementVPS13A disease and McLeod syndrome are related disorders caused by mutation of the VPS13A and XK genes, respectively. A pathologic VPS13A mutation disrupts binding of the VPS13A and XK proteins, suggesting a common basis of both diseases.

cell biology↗