Biology subjects

Jiang, K.

Publications and source records attributed to Jiang, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Janusein and EB Cooperate to Enhance Microtubule Plus-end Catastrophe

Microtubule (MT) plus ends are organized by end-binding (EB) proteins, yet how EB-associated factors modulate the transition from growth to catastrophe remains incompletely understood. Using spatially resolved proximity proteomics, we identified Janusein (ZC2HC1A) as a conserved, poorly characterized MT-associated protein (MAP). At low expression levels, Janusein tracked MT plus ends and reduced EB comet velocity; at higher levels, it redistributed to the MT lattice and was associated with MT bundling and widespread MT loss. Loss of Janusein resulted in spindle defects in human cells. In vitro, Janusein alone facilitated MT elongation through its C-terminal fragment, but promoted MT catastrophe through its N-terminal fragment in the presence of EB proteins. Molecular dynamics simulations and mutational analyses suggest that an N-terminal loop may perturb lateral contacts between adjacent MT protofilaments. Together, these findings identify Janusein as an unconventional MAP that functionally cooperates with EB proteins to promote MT catastrophe.

cell biology↗

bioRxiv2026

HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells

The transcription factor SOX10 is required for melanoma cell proliferation. However, SOX10 expression in single cells is heterogeneous, and low SOX10-expressing cells exhibit a dormant-invasive phenotype associated with drug resistance and metastasis. Despite longstanding interest in SOX10 as a diagnostic marker and potential therapeutic target in melanoma, the molecular mechanism and targets of SOX10 remain incompletely understood. New tools for the study and perturbation of SOX10 in cancer-relevant systems are needed to address these gaps in our knowledge. In this study, we engineered a patient-derived WW165 melanoma cell line for programmable SOX10 targeted proteolysis. We achieved this by replacing the endogenous copies of SOX10 with a SOX10-HaloTag transgene that supports cell growth, but can be rapidly degraded by the ubiquitin-proteasome system upon with a commercially available HaloPROTAC3 degrader molecule. We demonstrate that inducible degradation of SOX10-HaloTag faithfully recapitulates the known SOX10 transcriptional program, while also enabling discovery of SOX10 target genes previously undetected with standard genetic silencing approaches. We validated NAV2 and NCKAP5 as novel genes that are directly bound by SOX10 and coregulated with SOX10 expression in a patient cohort. This study demonstrates that new biological insights into the function of SOX10 can be enabled by targeted degradation and suggests that analogous approaches could prove powerful in the study of other transcription factors. We further suggest that the SOX10-HaloTag expressing melanoma cell line developed in this study could find further applications in investigating the consequences of SOX10 targeted degradation in vitro and in vivo.

biochemistry↗

bioRxiv2026

Protein Deimmunization with a Generative Diffusion Model

Protein immunogenicity is a major cause of biologic drug failure, leading to the production of anti-drug antibodies (ADA) that accelerate drug clearance, rejection of repeated doses, abolished efficacy, and sometimes life threatening anaphylaxis in patients. These responses constrain the clinical use of synthetic protein therapeutics from non-human origin. To efficiently deimmunize protein therapeutics, we developed a generative discrete diffusion model (MESSI), which takes protein structures as input and outputs sequences that preserve structure without containing peptides predicted to bind major histocompatibility complex class II molecules. MESSI designs sequences with high structural recovery and down to 0 predicted epitopes for specified MHC molecules at higher efficiency than post-hoc filtering approaches. Experimentally, we first applied MESSI to deimmunize a luciferase and a de novo designed mini-binder against PD-1, resulting in variants with no predicted epitopes and higher activity than their parents. Lastly, we coupled MESSI with evolution guidance to deimmunize uricase, a clinically approved enzyme with severe immunogenicity, and found deimmunized variants with higher catalytic activity than their natural orthologs. MESSI enables generative design of functional proteins with minimized immunogenicity, potentially making protein therapeutics safer and more effective.

bioengineering↗

bioRxiv2026

Grow2Fold: mapping heterogeneous developmental growth to human brain folding

Cortical folding emerges through complex developmental processes, yet what organizes these processes into the characteristic folding patterns of the human brain remains unclear. Here, we developed an imaging-informed whole-brain modeling framework, Grow2Fold, that integrates developmental cortical regionalization, quantitative growth characterization, and mechanics-guided simulation to investigate how cortical growth shapes brain folding patterns. Using 836 fetal and neonatal MRI sessions from 747 participants spanning 21-45 postmenstrual weeks, we identified a reproducible and hierarchical spatiotemporal organization of cortical expansion characterized by coordinated regional growth trajectories. Rapid expansion occurs earlier around peri-central territories and progressively shifts toward frontal, parietal, and temporal association cortices. We encoded these imaging-derived trajectories into region- and age-specific growth laws and incorporated them into anatomically realistic whole-brain mechanical models. The resulting simulations recapitulate major sulcal landmarks and characteristic folding development across global and regional morphological measures. Comparing regional and uniform growth, we find that differential growth drives cortical instability, while heterogeneous developmental growth organizes this instability into anatomically recognizable folding patterns. Combined with subject-specific anatomy, these population-informed growth laws reproduce individualized longitudinal folding trajectories. Together, our results identify spatiotemporally patterned developmental growth as a key spatial constraint on cortical morphogenesis and establish a quantitative bridge from developmental imaging, through mechanical instability, to anatomically organized folding.

biophysics↗

bioRxiv2026

The multiscale architecture of trait aggression: from meta-analytic convergence to multimodal characterization

Background. Trait aggression shows substantial interindividual variability, yet its neurobiological architecture across structural, functional, molecular, and macroscale organizational levels remains poorly understood. Methods. We developed a convergent multiscale framework to characterize the neurobiological architecture associated with trait aggression. We first integrated a large-sample voxel-based morphometry analysis (n = 922) with published neuroimaging studies using two complementary coordinate-based meta-analytic approaches, activation likelihood estimation and seed-based d mapping (total N = 3,671). Convergent meta-analytic findings were subsequently mapped onto functional connectivity networks, and their molecular signatures were characterized using imaging transcriptomics and neurotransmitter mapping. Finally, we examined whether the spatial organization of aggression-related networks was embedded within intrinsic multimodal brain hierarchies spanning morphometric, functional, transcriptomic, and neurochemical dimensions. Results. Across complementary analyses, trait aggression converged on a reproducible structural-functional network centered on the dorsomedial prefrontal cortex and dorsal anterior cingulate cortex. This architecture exhibited distinct molecular signatures, including gene-expression patterns enriched for synaptic functions and robust spatial associations with serotonergic, dopaminergic, and noradrenergic transporter systems. Moreover, the spatial organization of the aggression-related functional network was systematically predicted by the brain's intrinsic multimodal gradients, indicating that it is embedded within broader principles of cortical hierarchical organization. Conclusions. these findings move beyond the localization of aggression to discrete brain regions and identify a reproducible multiscale architecture linking aggression-related structural variation to functional network organization, molecular signatures, and the brain's intrinsic multimodal hierarchy. This integrative framework provides a systems-level account of the neurobiological basis of individual differences in trait aggression.

neuroscience↗

bioRxiv2026

Gradual evolution of multiplexed spatial coding within a conserved hippocampal scaffold

The hippocampus constructs spatial maps for navigation, yet their format differs markedly across species. Whether divergences reflect ecological adaptation, phylogenetic architecture, or flexible coding strategy within a conserved circuit has been difficult to disentangle. We recorded CA1 in rats and tree shrews (Tupaia belangeri chinensis), a mammal phylogenetically and ecologically between rodents and primates, using identical tasks and analyses. Unlike the position-dominant code of rats, tree shrew CA1 exhibited a hybrid representation: weaker position selectivity, stronger non-positional tuning, and prevalent multiplexing approaching primate characteristics. Multiplexed populations decoded location as accurately as rat position populations while using fewer neurons, suggesting computational advantages of high-dimensional coding. Despite this representational shift, proximo-distal gradient, pattern completion, and global remapping persisted. Representational format can be tuned without altering the underlying circuit. Tree shrews occupy an evolutionary intermediate in which ancestral network dynamics are repurposed for efficient multiplexed coding, tracing a transition toward primate-like spatial representations.

neuroscience↗

bioRxiv2026

Acute stress induces circuit-specific alterations in mesolimbic and nigrostriatal inhibitory transmission and potentiates operant learning

Acute stress can facilitate learning about stimuli that predict rewarding outcomes, yet whether stress similarly potentiates acquisition of reward-directed actions remains less well understood. Reward learning broadly depends on dopamine signaling within mesolimbic and nigrostriatal pathways. Dopamine transmission in the mesolimbic system is traditionally associated with cue-reward learning, whereas nigrostriatal dopamine signaling has been implicated in movement vigor and the acquisition of instrumental actions. Stress can alter dopamine transmission within these circuits and thereby influence reward learning. Previous work demonstrated that acute stress downregulates the potassium-chloride cotransporter KCC2 in ventral tegmental area GABA neurons. These stress-induced adaptations in inhibitory transmission enhance mesolimbic dopamine signaling and potentiate associative learning. Here, we show that prior exposure to acute restraint stress facilitates acquisition of operant sucrose self-administration in male and female rats. Enhanced learning was associated with increased temporal coincidence of GABA release events onto dopamine neurons and increased excitability of GABAergic inputs, alterations previously linked to enhanced dopamine signaling. These stress-induced adaptations exhibited marked circuit specificity within mesolimbic and nigrostriatal systems, selectively affecting inhibitory transmission onto dopamine neurons projecting to the nucleus accumbens lateral shell and dorsomedial striatum. Importantly, pharmacological enhancement of KCC2 function with CLP290 normalized inhibitory transmission within these pathways and attenuated stress-induced potentiation of operant learning. Together, these findings identify circuit-specific alterations in midbrain inhibitory signaling induced by acute stress that contribute to enhanced reward learning.

neuroscience↗

bioRxiv2026

A SIRT5-induced metabolic switch underlies chemoresistance and ATR checkpoint dependence in triple-negative breast cancer

Chemoresistance is the leading cause of poor prognosis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain unknown. To reveal metabolic drivers of de novo chemoresistance in TNBC, we analyzed pretreatment primary tumor biopsies, employing quantitative proteomics and metabolomics. Chemoresistant TNBCs exhibit hallmarks of oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism linked to overexpression of the mitochondrial sirtuin, SIRT5. Through gain- and loss-of-function studies and stable isotope tracing, we demonstrate that SIRT5 induces a coordinated metabolic switch that redirects glycolysis to the pentose phosphate pathway, thereby augmenting nucleotide pools, while enhancing glutaminolysis to support OXPHOS. Mechanistically, SIRT5 enhances conversion of 6-phospho-D-gluconate to ribulose-5-phosphate through demalonylation of 6-phosphogluconate dehydrogenase (6-PGD), and coordinately activates oncogenic c-MYC to promote glutamine utilization and dependence. Concurrently, SIRT5-induced nucleotide deregulation induces replication stress and hypersensitivity to ATR checkpoint activation, and ATR inhibition synergistically reverses chemoresistance in TNBC. Thus, elevated SIRT5 orchestrates a coordinated metabolic switch to expand nucleotide pools and drive chemoresistance, while producing ATR checkpoint dependence that represents a metabolic vulnerability of SIRT5-overexpressing TNBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/716852v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1c7a27corg.highwire.dtl.DTLVardef@17cb22borg.highwire.dtl.DTLVardef@1956670org.highwire.dtl.DTLVardef@1786dee_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Probiotic Lactiplantibacillus plantarum VB165 improves metabolic disorders in Insulin-Resistant Mice

This study investigated the effects of Lactiplantibacillus plantarum VB165, a probiotic strain with intrinsic -glucosidase inhibitor (AGI) activity, on metabolic disorders in high-fat diet (HFD)-induced insulin-resistant (IR) mice. Male C57BL/6 mice were divided into four groups: normal control diet (NCD), NCD supplemented with VB165, HFD, and HFD supplemented with VB165. After 16 weeks, VB165 supplementation significantly attenuated HFD-induced weight gain and reduced epididymal and inguinal white adipose tissue indices. VB165 also improved glucose intolerance and insulin resistance (IR), as demonstrated by oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT), and lowered fasting blood glucose, fasting insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels. Additionally, it ameliorated dyslipidemia by reducing serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), while alleviating hepatic steatosis and adipocyte hypertrophy. Mechanistically, VB165 enhanced intestinal barrier function by upregulating tight junction proteins (ZO-1 and Occludin), reduced systemic inflammation by lowering LPS, IL-6, and IL-1{beta}. Gut microbiota analysis revealed that VB165 modulated community composition, suppressing HFD-enriched genera (e.g., Ileibacterium and Coriobacteriaceae_UCG_002) and promoting beneficial taxa (e.g., Faecalibaculum and Oscillibacter). These findings demonstrate that L. plantarum VB165 improves HFD-induced metabolic disorders via multi-target mechanisms, highlighting its potential as a probiotic intervention for IR and related metabolic diseases.

microbiology↗

bioRxiv2026

Regulation of microtubule abundance and minus end dynamics by Katanin, CAMSAPs, WDR47 and kinesin-13

Microtubule networks are major determinants of cell architecture and logistics. Microtubule organization and density are regulated by severing enzymes, which cut microtubule lattices or affect their growth and shortening. These activities can lead to microtubule amplification or disassembly, depending on the presence of microtubule stabilizers or destabilizers, but the interplay between these factors is poorly understood. Here, we reconstituted in vitro the activity of microtubule severase katanin together with microtubule minus-end stabilizers CAMSAPs, their binding partner WDR47 and microtubule depolymerase kinesin-13/MCAK. We confirmed that katanin can amplify or destroy microtubules in a concentration-dependent manner. CAMSAPs recruit katanin to microtubules and reduce katanin concentration needed for both amplification and destruction, whereas kinesin-13 completely abolishes microtubule amplification. WDR47 binds to microtubules decorated by CAMSAPs and suppresses katanin binding and severing. In addition, both katanin and WDR47 inhibit polymerization of CAMSAP-decorated microtubule minus ends. These data explain how these proteins act together to fine-tune microtubule minus-end stability without strongly increasing microtubule abundance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/714132v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@746fe3org.highwire.dtl.DTLVardef@5dd5a8org.highwire.dtl.DTLVardef@762373org.highwire.dtl.DTLVardef@1192db_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cell biology↗

bioRxiv2026

Ancestral secretory programs underlie the evolution of morphological innovations across Spiralia

Understanding how morphological innovation arise from ancestral genetic and cellular systems remains a major challenge in evolutionary biology. Molluscan shells represent one of the most diverse morphological novelties within Spiralia and have been central to the ecological and evolutionary diversification of molluscs. However, the cellular basis of shell formation and the evolutionary origin of shell-forming cell types remain poorly understood. Here, we present a single-cell transcriptomic atlas of the Pacific oyster (Crassostrea gigas) mantle and show that molluscan shell-forming cell types are evolutionarily recent innovations built upon ancestral epithelial secretory systems of spiralians. We identify five spatially segregated shell-forming epithelial cell types, and demonstrate that larval and adult shell-forming cells are developmentally independent and characterized by transcriptomes enriched for evolutionarily young genes. Cross-species cell-type comparisons further reveal that oyster shell-related genes are embedded within conserved epithelial and secretory programs across spiralians. Together, we propose that a substantial genetic foundation for shell formation was already present in the last common ancestor of Spiralia, and that molluscan shell diversity arose through repeated co-option of ancestral genetic programs coupled with novel genes. Our study provides a framework for understanding how ancient cellular architectures can be repeatedly reconfigured to generate morphological novelty during evolution.

evolutionary biology↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Compartmentalized cytokine networks and systemic immune remodeling in bovine mammary H5N1 infection.

Highly pathogenic avian influenza A H5N1 has recently expanded its mammalian host range; in 2024, genotype B3.13 emerged in U.S. dairy cattle with pronounced mammary tropism. In the past, Influenza A virus immunology has been characterized primarily in respiratory infection models, whereas this study delineates immune responses after intramammary infection. An intramammary H5N1 challenge in Jersey cows in the early dry-off period enabled integration of dose- and compartment-resolved (alveoli versus teat cistern) cytokine and chemokine profiles with peripheral leukocyte dynamics and H5/N1-specific antibody responses. Infection-induced quarter-restricted, monophasic inflammatory networks peaking at 3-7 days post-infection, coordinated peripheral myeloid expansion and IFN-{gamma}-competent lymphocyte activation, and rising antibody titers across quarters.

microbiology↗

bioRxiv2026

IR-B deficiency and fatty acid dysregulation accelerate prostate cancer progression via PI3K/AKT signaling

The insulin receptor (IR) is markedly overexpressed in both human and mouse prostate cancer, with a significant elevation in the IR-A/IR-B ratio across patient tissues, cell lines, and Hi-Myc mouse prostates. To elucidate the role of IR-B in prostate tumorigenesis, we generated a prostate-specific IR-B knockout (KO) mouse model using Pbsn-Cre-driven recombination. Prostate-restricted loss of IR-B was confirmed at the transcript level and did not affect other tissues. Crossing these mice with Hi-Myc transgenics revealed that IR-B deficiency promotes accelerated progression to invasive adenocarcinoma, characterized by enhanced cellular proliferation and atypical histopathology. Transcriptomic and metabolomic profiling of dorsolateral prostate lobes demonstrated activation of PI3K/AKT and mTOR signaling, along with upregulation of IRS1/2/4 and IGF2. Metabolite analyses indicated elevated fatty acid levels and enhanced lipolysis pathways, implicating metabolic reprogramming in tumor progression. Notably, glucose and lipid metabolism genes, including GLUT1, GLUT12, FASN, and GPR120, were upregulated, accompanied by an increased BCL2/BAX ratio, suggesting apoptosis inhibition. Functional studies further revealed opposing roles of dietary fatty acids: {omega}-3 polyunsaturated fatty acids (EPA, DHA) suppressed prostate cancer cell survival, proliferation, and PI3K/AKT signaling while promoting apoptosis, whereas {omega}-6 fatty acid (arachidonic acid) exerted pro-tumorigenic, anti-apoptotic effects. Collectively, these findings identify IR-B loss as a driver of metabolic and signaling reprogramming that accelerates prostate tumorigenesis, while highlighting {omega}-3 fatty acids as potential modulators counteracting IR-B-deficient prostate cancer progression.

cancer biology↗

bioRxiv2026

Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling

Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.

cell biology↗

bioRxiv2025

Highly Consistent Anatomical Asymmetry in a Small Primate Brain: Left is Always Larger in the Marmoset Monkey

Although lateralisation of brain function is relatively common in animals, this is rarely accompanied by overt anatomical asymmetries. In primates, morphological differences between the cerebral hemispheres are well established in Hominidae but have been regarded as subtler or inconsistent in other species. Here we demonstrate that the left hemisphere is reproducibly larger than the right hemisphere in one of the smallest primates, the marmoset. This asymmetry develops postnatally, persists throughout adult life, and is found in individuals from genetically isolated colonies. Voxel-based morphometry reveals that the larger left hemisphere is primarily due to differences in the volume of cortical areas linked to social cognition. This result challenges the notion that the development and evolution of marked morphological asymmetry between the hemispheres is linked to the evolution of large brains.

neuroscience↗

bioRxiv2025

Disruption of ADAMTSL4 Causes Ectopia Pupillae in Zebrafish via COL8A1-Driven Cell Migration

Congenital ectopia lentis (EL) poses a significant threat to visual outcomes in children. Although emerging causative genes have been identified, their biological functions remain poorly understood. In this study, we investigated the contribution of ADAMTSL4 variants to congenital EL in a cohort of 702 pedigrees. Pathogenic variants in ADAMTSL4 were identified in 23 probands (3.28%), comprising 29 distinct variants, with 14 being novel, making ADAMTSL4 the second most frequently mutated gene in the cohort. All affected individuals exhibited EL, and 26.09% also presented with ectopia pupillae (EP), also referred to as ectopia lentis et pupillae. To explore the functional consequences of ADAMTSL4 deficiency, we generated a CRISPR/Cas9-mediated adamtsl4-knockout zebrafish model, that faithfully recapitulated cardinal human disease features with an incidence comparable to that observed in affected patients. Histological and ultrastructural analysis revealed disrupted zonular fiber anchorage at the lens capsule, even in mutated eyes without overt EL or EP. Transgenic overexpression of adamtsl4 successfully reversed the ocular phenotypes, confirming the genes essential role in ocular development. Single-cell RNA-sequencing and fluorescence in situ hybridization demonstrated enriched ADAMTSL4/adamtsl4 expression in the equatorial lens epithelium, retinal pigment epithelium (RPE), iris anterior pigmented epithelium, and choroid fibroblast. Functional assays using zebrafish and human RPEs revealed that ADAMTSL4 deficiency compromised cell adhesion and promoted cell migration. Transcriptomic profiling revealed significant enrichment of extracellular matrix organization and cell adhesion pathways, with cross-species validation identifying consistent upregulation of COL8A1/col8a1b. Notably, COL8A1 knockdown in ADAMTSL4-deficient RPEs partially reversed the aberrant migratory phenotype, suggesting a functional interaction. Together, these findings establish ADAMTSL4 as a major causative gene in ectopia lentis et pupillae, highlight its role in orchestrating ocular integrity via regulation of extracellular matrix and cell behavior.

genetics↗

bioRxiv2025

Reelin Controls the Directional Orientation, Apical Localization and Length of Primary Cilia in Principal Neurons in the Cerebral Cortex

The primary cilia of pyramidal neurons in inside-out laminated regions orient predominantly toward the pia, reflecting reverse soma movement during postnatal neurodevelopment. However, the mechanisms underlying the directional cilia orientation are unknown. Here we show that the primary cilia of pyramidal neurons are localized near the base of the apical dendrites and aligned on the nuclear side opposite to the axon initial segment (AIS). However, this pattern is not observed in atypical pyramidal neurons in the deep neocortex, excitatory neurons in non-laminated regions, interneurons, or astrocytes, where cilia are irregularly positioned around the nuclei and lack preferred orientation. In Reelin-deficient mice (reeler), the directional orientation and apical location of cilia in late-born neocortical and CA1 neurons are disrupted. However, the initial impairments are partially corrected during postnatal development, along with a realignment of apical-basal orientation. In contrast, loss of Reelin drastically disrupts the directional orientation of cilia in early-born neocortical neurons and principal neurons in evolutionarily conserved cortical regions, which lack postnatal correction. Consistently, their cilia do not preferably localize to the apical side. Additionally, Reelin deficiency increases the cilia length of principal neurons across the cerebral cortex at a developmental stage when cilia stabilize in wild-type mice, but this effect is not observed in interneurons, astrocytes, or excitatory neurons in non-laminated regions. Together, Reelin controls the directional orientation, apical localization, and length of primary cilia in principal neurons in the cerebral cortex, underscoring the cilium as a key apical domain particularly prominent in late-born neurons.

neuroscience↗