Biology subjects

Lim, Y.

Publications and source records attributed to Lim, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Blockade of Kv3.1 by MK-801, a PCP-Derivative NMDA Receptor Inhibitor: Implications for Models of Schizophrenia

MK-801, a phencyclidine (PCP) derivative also known as dizocilpine, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). The NMDAr plays a critical role in mediating excitatory synaptic transmission in the central nervous system (CNS) and is important in regulating synaptic plasticity, learning, and memory. MK-801 is known to induce schizophrenia-like phenotypes in animal models by blocking the NMDAr. Several studies have reported that the cognitive impairment associated with schizophrenia is linked to functional defects of ion channels in parvalbumin-positive GABAergic interneurons. Kv3.1 is a voltage-gated K+ (Kv) channel involved in the rapid repolarization of the action potential in neurons; it is richly expressed in parvalbumin-positive GABAergic interneurons and is associated with fast, repetitive spike generation. A decrease of Kv3.1 in the CNS has been reported to be associated with schizophrenia. In the present study, the effect of MK-801 on Kv3.1 was investigated using the whole-cell patch-clamp technique in Chinese hamster ovary (CHO) cells stably expressing Kv3.1. MK-801 caused a concentration-dependent inhibition of Kv3.1, with an IC50 of 10.81 M and a Hill coefficient of 0.89. The blocking potency was stronger at depolarized potentials, indicating a voltage-dependent block. MK-801 also produced a use-dependent block, inducing progressive inhibition with repeated stimulation at increased frequencies (1 Hz and 2 Hz), consistent with a delay in recovery from inactivation of Kv3.1 in the presence of MK-801. In addition, MK-801 induced a hyperpolarizing shift in the voltage dependence of the steady-state inactivation curve of Kv3.1. Taken together, these results indicate that MK-801 blocks Kv3.1 expressed in CHO cells in a concentration-, voltage-, and state-dependent manner. Given the importance of Kv3.1 in parvalbumin-positive, fast-spiking GABAergic interneurons, these findings suggest that MK-801 may alter the firing patterns of these inhibitory neurons, contributing to the onset and symptoms of schizophrenia.

pharmacology and toxicology↗

bioRxiv2026

Lyophilization Maintains the Storage Stability and Bioactivity of Mesenchymal Stem Cell–Derived Extracellular Vesicles

BackgroundExtracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are emerging therapeutic candidates for bone regeneration, but their long-term stability remains a barrier to clinical translation. This study evaluated whether lyophilization supports the stable storage of extracellular vesicles derived from human epidural fat MSCs (hEF-MSCs) cell line. Research Design and MethodsEVs were isolated, lyophilized with 8.5 % sucrose and HEPES(4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), and stored for 3 months at -80, -20, 4, and room temperature (20). After reconstitution in phosphate-buffered saline (PBS), structural characteristics were assessed using transmission electron microscopy, nanoparticle tracking analysis, and flow cytometry. Functional activity was evaluated using MC3T3-E1 osteogenic differentiation assays. The main outcome measures included morphology, particle counts, marker expression, cytotoxicity, and sequencing profiles. ResultsLyophilization maintained EV morphology, structural integrity, and particle distribution across all storage temperatures. Marker expression remained comparable among the conditions. Reconstituted EVs promoted osteogenic differentiation of MC3T3-E1 cells without evidence of cytotoxicity. Sequencing profiles revealed no significant differences among storage conditions. ConclusionsLyophilized EVs from hEF-MSCs cell lines exhibited stable structural and functional properties across a range of storage temperatures, supporting their suitability for further development in bone regeneration applications.

Molecular Biology↗

bioRxiv2026

Lyophilized Extracellular Vesicles Retain Regenerative Activity and Accelerate Wound Healing

Extracellular vesicles (EVs) are promising therapeutic agents for tissue regeneration because they regulate intercellular communication and modulate inflammatory responses. However, preserving EV bioactivity during long-term storage remains a major barrier to clinical application. We examined whether lyophilized EVs stored at -80 {degrees}C maintain their structural integrity and therapeutic efficacy in an in vivo wound-healing model. Mesenchymal stem cell-derived EVs were isolated and freeze-dried before storage at -80 {degrees}C. We evaluated EV physicochemical characteristics before and after lyophilization using nanoparticle tracking analysis, transmission electron microscopy, and EV marker-expression analysis. To assess regenerative efficacy, lyophilized EVs were applied topically to full-thickness ear wounds in CCR2-GFP mice. Wound-healing progression and CCR2-positive cell infiltration were monitored during tissue recovery using intravital microscopy. Lyophilized EVs preserved their characteristic morphology, particle-size distribution, and EV surface marker expression after storage. In vivo analysis showed that EV-treated wounds closed significantly faster than phosphate-buffered saline-treated controls. Additionally, lyophilized EV treatment reduced CCR2-positive inflammatory cell recruitment during healing, suggesting an immunomodulatory role in tissue regeneration. These findings show that EVs lyophilized and stored at -80 {degrees}C retain biological function and therapeutic potential in vivo. Lyophilized EVs may, therefore, provide a practical strategy for long-term storage and delivery of EV-based regenerative therapeutics.

Cell Biology↗

bioRxiv2026

Intron 13 retention expands the ADAR1 isoform repertoire to rewire PKR signaling and promote tumorigenesis

For decades, the biology of ADAR1 has been framed around two major isoforms: the nuclear-enriched p110 and the predominantly cytoplasmic p150. Here, we reveal an unexpected repertoire expansion of ADAR1 isoforms that is driven by intron retention. Specifically, intron 13 (I13) can be retained in ADAR1 transcripts, conferred by an evolutionarily conserved weaker 5SS. In addition, we found that the I13 retention (I13R) is negatively autoregulated by ADAR1 through antagonizing the binding of hnRNPA1 to I13 in an editing-independent manner. Despite being sensitive to nonsense-mediated decay, I13R generates two previously uncharacterized truncated isoforms - p90 and p130, that both lack the C-terminal portion of the deaminase domain. Intriguingly, ADAR1p90 - a derivative of the canonical nuclear-enriched p110 isoform - is predominantly cytoplasmic, that effectively represses PKR and eIF2 activation through the sequestration of immunogenic double-stranded RNA (dsRNA) substrates. Furthermore, in a colorectal cancer (CRC) cohort, p90 levels are increased in most tumors relative to matched normal tissues that positively correlates with hnRNPA1 expression. Functionally, xenografts expressing ADAR1p90 grow significantly faster and larger than those expressing ADAR1p110, indicating enhanced tumorigenic potential. These findings revise the canonical view of ADAR1 isoforms, demonstrating that intron retention can generate alternative isoforms with augmented functions that tumors readily exploit. One Sentence SummaryThe conserved retention of I13 in ADAR1 transcripts gives rise to previously uncharacterized C-terminal truncated cytoplasmic ADAR1 isoforms, p90 and p130, which, although devoid of catalytic activity, sequester immunogenic dsRNA substrates, thereby preventing PKR binding and downstream activation of eIF2.

cell biology↗

bioRxiv2026

An optimized three-laser 27-color spectral flow cytometry panel for multi-organ profiling in mice

While high-dimensional flow cytometry plays critical roles in resolving complex cellular networks, there remains a scarcity of comprehensive panels for the simultaneous profiling of diverse mouse cell types, primarily due to the inherent difficulty of multiplexing. To address this technical gap and resolve diverse cell populations in murine models, we designed a 27-color flow cytometry panel optimized for 3-laser spectral flow cytometers. This optimized panel enables broad and simultaneous detection of 16 distinct cell subsets from both lymphoid and myeloid lineages--including T cells, B cells, plasma cells, NK cells, innate lymphoid cells, dendritic cells, monocytes, macrophages, neutrophils, eosinophils, basophils, mast cells--along with non-immune cells, such as epithelial, endothelial, fibroblast, and neuronal cells. The panel has been successfully applied to various tissues, including spleen, thymus, bone marrow, peripheral blood, mesenteric lymph nodes, peritoneal lavage fluid, gut epithelium, and lamina propria. Applying this panel to a poly(I:C) model, we successfully tracked dynamic shifts in monocyte and neutrophil populations and identified a previously unrecognized, glucocorticoid-producing cell subset via reporter expression. This panel will facilitate high-dimensional immune profiling on standard 3-laser cytometers, providing a robust tool for dissecting cellular dynamics across diverse contexts.

immunology↗

bioRxiv2026

Cultivation and genomic characterization of the first representative of the globally distributed marine UBA868 group

Members of the UBA868 group within the order Arenicellales are globally distributed marine Gammaproteobacteria predicted to participate in sulfur and carbon cycling, yet their physiology and ecological roles remain unknown due to the absence of cultured representatives. Here, we report the isolation and characterization of the first heterotrophic representative of the previously uncultured UBA868 group. Using dilution-to-extinction cultivation, we obtained four isolates from the Yellow Sea whose high-quality genomes represent a single UBA868 species. One strain, IMCC57338, maintained in axenic culture, exhibited small coccoid morphology and slow growth (doubling time [~]2.9 days), consistent with an oligotrophic lifestyle. Genome analysis revealed a predominantly aerobic chemoorganoheterotrophic lifestyle with a streamlined central carbon metabolism, including a complete glyoxylate shunt and limited carbohydrate utilization capacity, suggesting adaptation to low-nutrient conditions. The genome also encodes pathways for methylated amine oxidation coupled to formaldehyde assimilation via the serine cycle, indicating a capacity for methylotrophy. Genes encoding sulfur oxidation (Sox) and reverse dissimilatory sulfite reductase (rDsr) pathways further suggest a capacity for sulfur-based chemolithoheterotrophy. Global metagenomic and metatranscriptomic read recruitment showed that the species represented by IMCC57338 is widely distributed across ocean basins and pelagic depth layers, with higher abundance and transcriptional activity in mesopelagic waters. Our findings provide the first physiological and genomic insights into the UBA868 group and suggest that members of this lineage contribute to the cycling of organic carbon, C1 compounds, and sulfur in marine ecosystems.

microbiology↗

bioRxiv2026

Cross-cohort analysis reveals conserved gut virome signatures and phage-encoded auxiliary functions in ulcerative colitis

While gut bacteriome dysbiosis is a well-established hallmark of ulcerative colitis (UC), the ecological and functional remodeling of the gut virome conserved across diverse populations remains unclear. Here, by constructing a cross-cohort atlas of the UC-associated fecal virome, we show that viral reorganization closely parallels bacterial dysbiosis, with enrichment of phages targeting disease-associated bacterial taxa. We identified a conserved set of UC-associated viral signatures that robustly distinguished UC from healthy controls using machine-learning-based classification across independent cohorts. Functional profiling further revealed that phages enriched in UC carried higher densities of auxiliary metabolic genes (AMGs) related to virulence and antibiotic resistance than phages depleted in UC, with immune evasion and glycopeptide resistance genes particularly overrepresented. Together, our cross-cohort approach highlights the value of the gut virome-based diagnostic framework for UC and suggests that phage-encoded AMGs may contribute to shaping the gut ecosystem under inflammatory conditions.

microbiology↗

bioRxiv2026

Prime-Target neoantigen vaccination unleashes unprecedented T cell immunity within ''cold'' immunosuppressive tumors

"Cold" immunosuppressive solid tumors are hard-to-treat cancers that are non-responsive to immunotherapies. Their immunosuppressive tumor microenvironment (TME) excludes and inhibits T cells and thereby hampers the therapeutic efficacy of cancer vaccines and immune checkpoint blockade. To overcome this, we employed a "Prime-Target" (P/T) neoantigen vaccination strategy that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations to first prime potent systemic neoantigen-specific T cell immunity and then trigger intratumoral T cell recruitment. Using immunotherapy non-responsive murine tumor models with pronounced immunosuppressive TMEs, we demonstrate that P/T neopeptide vaccination resulted in extraordinary tumor control and TME remodeling. P/T vaccination elicited strong systemic anti-tumor responses as well as potent and rapid recruitment of clonal CD4+ Th1 and non-exhausted CD8+ T cells into tumors that carried novel T cell receptors (TCR) and were vaccine neopeptide-specific. Concurrently, P/T vaccination reshaped the TME by decreasing suppressive Treg and M2 macrophages, and dramatically increasing the ratio of effector T cells to Treg and M2 macrophages. Vaccination-induced tumor control was neopeptide-dependent and required concurrent IT administration of both neopeptides and adjuvants. Our study highlights P/T neoantigen vaccination as a promising strategy to overcome T cell exclusion within "cold" immunosuppressive solid tumors and thereby unleash unprecedented anti-tumor immunity.

immunology↗

bioRxiv2025

AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration

Glaucoma is a leading cause of irreversible blindness, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Mitochondrial dysfunction plays a central role in this neurodegeneration, yet effective targeted therapies remain limited. Here, we identify the mitochondrial scaffold A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience and axon regeneration. AKAP1 expression is diminished in human glaucomatous retinas and experimental glaucoma models, correlating with elevated intraocular pressure, disrupted mitochondrial dynamics, oxidative stress, and synaptic instability. Restoration of AKAP1 via adeno-associated virus serotype 2-mediated gene therapy preserves RGC survival, promotes mitochondrial fusion and cristae integrity, enhances ATP production, and mitigates oxidative and apoptotic stress in mouse models of glaucoma and optic nerve injury. Transcriptomic profiling of AKAP1 knockout retinas reveals widespread dysregulation of mitochondrial and synaptic gene networks. Mechanistically, AKAP1 stabilizes synapses by promoting mitochondrial biogenesis, modulating calcium/calmodulin-dependent kinase II and synapsin phosphorylation, maintaining synaptophysin expression, and suppressing complement component C1q expression, thereby preventing early synaptic loss in glaucomatous neurodegeneration. Moreover, restoring AKAP1 expression facilitates axonal regeneration, preserves the central visual pathway, and maintains visual function. Collectively, these findings establish AKAP1 as a master regulator of mitochondrial and synaptic homeostasis and axonal regeneration and a promising therapeutic target for vision preservation in glaucomatous neurodegeneration. One Sentence SummaryAKAP1 protects retinal ganglion cells and preserves vision by restoring mitochondrial and synaptic health in experimental glaucoma models.

neuroscience↗

bioRxiv2025

Proteome-wide in silico screening for human protein-protein interactions

Protein-protein interactions (PPIs) drive virtually all biological processes, yet most PPIs have not been identified and even more remain structurally unresolved. We developed a two-step computational screen for human PPIs. First, a classifier called KIRC (Knowledge-Informed Rapid Classifier), trained on biological features, was used to rank all 200 million possible protein pairs in the human proteome by their interaction likelihood. Second, the [~]1.6 million top-ranked KIRC pairs were subjected to structure prediction by AlphaFold-Multimer and ranked using SPOC (Structure Prediction and Omics Classifier), which identifies functional predictions based on biological and structural features. This pipeline revealed 16,000 high-confidence PPIs ([~]90% precision), of which more than 5,000 were not previously recognized and more than 12,000 have not been structurally resolved. We use this "predictome" to formulate new hypotheses in different areas of biology, reinterpret low-resolution cryo-EM maps, and identify and validate novel PPIs that may support replication-coupled chromatin assembly. The predicted PPIs, viewable at predictomes.org, are expected to accelerate characterization of the molecular interactions that underlie vertebrate cell physiology.

bioinformatics↗

bioRxiv2025

Host transcriptional responses to gut microbiome variation arising from urbanism

Gut microbiomes of urban communities are compositionally different from their rural counterparts, and are associated with immune dysregulation and gastrointestinal disease. However, it is unknown whether these compositional differences impact host physiology, and through what mechanisms. Here, we used human colonic epithelial cells to directly compare host transcriptional changes induced by gut microbiomes from urban versus rural communities. We co-cultured host cells with live, stool-derived gut microbiomes from Rwanda, Ghana, Nigeria, Malaysia, and the United States, and quantified transcriptional responses using RNA-seq. We found that urban microbiomes affected innate immune pathways, including TNF signaling and bacterial antigen recognition. We also found that high-diversity microbiomes elicited a stronger host transcriptional response, while low-diversity microbiomes triggered epithelial restructuring and glycolysis. Finally, specific taxa driving these effects, including Bifidobacterium adolescentis and Bacteroides dorei, correlated with lifestyle factors such as diet. These findings demonstrate that urbanization-associated microbiome changes directly influence host epithelial gene expression.

microbiology↗

bioRxiv2025

Cranial suture integrity is maintained by Fgfr3 in zebrafish

Cranial suture formation is a dynamic process requiring precise cellular and molecular coordination to regulate bone growth and suture homeostasis. Despite the recognized role of Fibroblast Growth Factor Receptor 3 (FGFR3) in this process and its association with Muenke syndrome, one of the most common syndromic craniosynostoses, its precise function remains undefined. Through analyses of cranial suture formation and maintenance in a fgfr3 LoF zebrafish model displaying abnormal suture morphology, we demonstrate for the first time that Fgfr3 plays a pleiotropic role during these events. Transmission electron microscopy and second harmonic generation imaging revealed that Fgfr3 is involved in the proper organization of the collagen network within the suture. By employing specific transgenic reporter lines and studying gene expression of suture mesenchymal stem cell markers via RNAscope in situ hybridization, we show that Fgfr3 is crucial for regulating osteogenesis within the suture. Specifically, Fgfr3 limits the number of osteoprogenitors at the osteogenic front and promotes osteoblast maturation at the suture edge. Finally, our results reveal that Fgfr3-mediated regulation of osteogenesis involves cross-talk between FGF, canonical Wnt, and potentially BMP signaling pathways. In conclusion, these data position Fgfr3 as a central regulator of cranial suture formation and open new perspectives for understanding suture homeostasis and FGFR3-related craniosynostoses.

developmental biology↗

bioRxiv2024

Effects of Age and Cognitive Functions on the Neural Tracking of Speech in Noise

Older adults often struggle to comprehend speech in noisy environments, a challenge influenced by declines in both auditory processing and cognitive functions. This study examines age-related differences in speech recognition in noise, focusing on the roles of delta (1-4 Hz) and theta (4-8 Hz) neural oscillations and their relationship with cognitive function, particularly working memory. Electroencephalography (EEG) was used to collect data from 23 young adults (20-35 years) and 23 older adults (65-80 years) with normal hearing. Cognitive assessments were administered to older adults, and both groups completed an EEG task involving speech recognition in Speech-Shaped Noise (SSN) at individualized noise levels based on their Sentence Recognition Scores (SRS). Results showed that age significantly impacted hit rates and reaction times in noisy speech recognition tasks. Theta-band neural tracking was notably stronger in older adults, while delta-band tracking showed no age-related difference. Pearsons correlations indicated significant associations between age-related cognitive decline, reduced hearing sensitivity, and Mini-Mental State Examination (MMSE) scores. Regression analyses showed that theta-band neural tracking at specific SRS levels significantly predicted word list recognition in the higher SRT group, while constructional recall was strongly predicted in the lower SRT group. The findings suggest that older adults may rely on theta-band neural tracking as a compensatory mechanism to support speech perception in noise, with indirect links between working memory and speech perception. Further research is needed to explore the causal relationship between cognitive function and hearing.

neuroscience↗

bioRxiv2024

TTF2 promotes replisome eviction from stalled forks in mitosis

Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its non-catalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase {varepsilon} in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.

biochemistry↗

bioRxiv2024

Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis

Cellular senescence, marked by irreversible cell cycle arrest and the secretion of proinflammatory factors, contributes to aging and cancer recurrence. Chemotherapy can also induce senescence; senescent cells often resist apoptosis and promote tumor recurrence. The interaction between FOXO4 and p53 sustains cell survival. Herein, we used biophysical techniques and conducted cellular experiments to develop a peptide inhibitor targeting this interaction to eliminate senescent cancer cells. We identified key regions in the p53 transactivation domain (TAD) involved in FOXO4 binding and designed an optimized peptide inhibitor (CPP-CAND) with improved cell permeability. CPP-CAND showed high selectivity and potency in inducing apoptosis in senescent cells by disrupting FOXO4-p53 foci and activating caspase pathways. It is effective against senescent cancer cells induced by doxorubicin and cisplatin, highlighting its potential as a senolytic drug. Thus, CPP-CAND is a promising therapeutic candidate with improved selectivity, efficacy, and cost-effectiveness.

biochemistry↗

bioRxiv2024

Massively parallel screening of TIR-derived peptides reveals vast TLR-targeting immunomodulatory peptides

Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast unsequenced space of the TIR domain family. Here, we developed a comprehensive parallel screening method to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. We constructed a large peptide library, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIR and MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling, demonstrated anti-inflammatory effects in macrophages and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.

molecular biology↗

bioRxiv2024

A 3D in vitro assay to study combined immune cell infiltration and cytotoxicity

Immune cell-mediated killing of cancer cells in a solid tumor is prefaced by a multi-step infiltration cascade of invasion, directed migration, and cytotoxic activities. In particular, immune cells must invade and migrate through a series of different extracellular matrix (ECM) boundaries and domains before reaching and killing their target tumor cells. These infiltration events are a central challenge to the clinical success of CAR T cells against solid tumors. The current standard in vitro cell killing assays measure cell cytotoxicity in an obstacle-free, two-dimensional (2D) microenvironment, which precludes the study of 3D immune cell-ECM interactions. Here, we present a 3D combined infiltration/cytotoxicity assay based on an oil-in-water microtechnology. This assay measures stromal invasion following extravasation, migration through the stromal matrix, and invasion of the solid tumor in addition to cell killing. We compare this 3D cytotoxicity assay to the benchmark 2D assay through tumor assembloid cocultures with immune cells and engineered immune cells. This assay is amenable to an array of imaging techniques, which allows direct observation and quantification of each stage of infiltration in different immune and oncological contexts. We establish the 3D infiltration/cytotoxicity assay as an important tool for the mechanistic study of immune cell interactions with the tumor microenvironment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/586980v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@6a161dorg.highwire.dtl.DTLVardef@d1e5d3org.highwire.dtl.DTLVardef@47b87corg.highwire.dtl.DTLVardef@a0e051_HPS_FORMAT_FIGEXP M_FIG The 3D combined infiltration/cytotoxicity assay captures three important steps of immune cell infiltration into the solid tumor microenvironment: (1) circulating immune cells extravasate and invade the stromal matrix, (2) immune cells migrate through the stromal matrix to reach the tumor core, and (3) immune cells that successfully navigate the stroma must cross a basement membrane boundary secreted by the cancer cells to contact and kill the cancer cells within a solid tumor. C_FIG

cancer biology↗

bioRxiv2024

ARX regulates interneuron subtype differentiation and migration

Mutations in aristaless-related homeobox (ARX) are associated with neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorders, with or without brain malformations. Aspects of these disorders have been linked to abnormal cortical interneuron (cIN) development and function. To further understand ARXs role in cIN development, multiple Arx mutant mouse lines were interrogated. We found that ARX is critical for controlling cIN numbers and distribution, especially, in the developing marginal zone (MZ). Single cell transcriptomics and ChIP-seq, combined with functional studies, revealed ARX directly or indirectly regulates genes involved in proliferation and the cell cycle (e.g., Bub3, Cspr3), fate specification (e.g., Nkx2.1, Maf, Mef2c), and migration (e.g., Nkx2.1, Lmo1, Cxcr4, Nrg1, ErbB4). Our data suggest that the MZ stream defects primarily result from disordered cell-cell communication. Together our findings provide new insights into the mechanisms underlying cIN development and migration and how they are disrupted in several disorders.

neuroscience↗