Biology subjects

Zhang, M.

Publications and source records attributed to Zhang, M..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

Highly Adaptive Conductive Polymer Electronics Enhance Neural Data and Learning Accuracy

Human skin, the bodys largest organ, plays a vital role in sensing and transmitting neuronal, mechanical, and biochemical signals, making it an essential non-invasive interface for health monitoring, rehabilitation, and human-machine interaction. However, aging-related changes, including thinning, increased wrinkling, dryness, and altered collagen structure, significantly impact electrical impedance, conductance, and contact stability, challenging the fidelity and consistency of bioelectronic signal acquisition. Here, we address this gap by developing "AdapSkin," an age-adaptive, skin-mimicking, bio-adhesive, and stretchable polymeric electronic skin interface that seamlessly conforms to diverse skin properties, enabling high-fidelity and high-density electrophysiological recording. The soft electrodes of AdapSkin are composed of an aqueously processed, homogeneously mixed organic nanocomposite with a conductive polymer percolation network, forming a gel-like interface that reduces modulus and enhances skin-electrode contact. The materials platform achieves extraordinary softness and electrical stretchability of up to 1200% through a double-network composite structure. AdapSkin significantly minimizes age-induced variations in interfacial impedance and signal-to-noise ratio (SNR), improving signal consistency for neuromuscular assessment, prosthetic control, and rehabilitation applications. Scalable fabrication enables the creation of large-area electrode arrays, which reduces motion artifacts, improves sEMG mapping reliability, and ensures long-term signal stability across various age groups. Machine learning analysis further demonstrates AdapSkins superior accuracy in gesture classification for elderly users, highlighting its potential to enhance prosthetic control, assistive robotics, and rehabilitation for individuals with sarcopenia and neuromuscular decline. By improving signal quality and adaptability in aging populations, AdapSkin advances fair bioelectronic interfaces, fostering more equitable and effective healthcare technologies for age-related conditions.

bioengineering↗

bioRxiv2025

Senescent Activated Naive B Cells Promote Anti-Citrullinated Antigen T Cell Responses and the Transition to Clinical Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by joint and systemic inflammation. Anti-citrullinated protein antibodies (ACPAs) define an at-risk stage that precedes clinically apparent inflammatory arthritis (clinical RA) onset, yet the molecular mechanisms driving progression remain poorly understood. Here, we applied single-cell multi-omics to profile B cells longitudinally collected from ACPA individuals who either convert to clinical RA (Converters) or do not (Nonconverters). We identified a striking expansion of CXCR5CD69 activated naive B cells (aNAVs) uniquely in Converters prior to clinical RA. These aNAVs exhibited a pro-inflammatory, senescent transcriptional program and persist through to clinical RA. In Converters, aNAVs expressed polyreactive, autoreactive IgM with distinctive V-J gene rearrangements that dominate the BCR repertoire. Furthermore, in Converters most IgM aNAVs were developmentally arrested in the peripheral blood, while a subset undergoes class switching and follows divergent somatic hypermutation trajectories. Mechanistically, aNAVs infiltrated RA synovium and served as potent antigen presenting cells to activate both anti-citrullinated antigen CD4 and CD8 T cells in an HLA-dependent manner. Chronic exposure to citrullinated antigens and CpG synergistically drove aNAV activation and senescence. These findings establish a mechanistic link between naive B cell senescence and clinical RA development in ACPA+ individuals, providing a rationale for therapeutically targeting aNAV B cells for the prevention of RA. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/682430v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@153b185org.highwire.dtl.DTLVardef@1aba6eeorg.highwire.dtl.DTLVardef@5c886eorg.highwire.dtl.DTLVardef@10109a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

BubR1 TPR domain supports mitotic checkpoint by promoting MCC formation and MCC-APC/C interaction

BubR1 is the key component of the mitotic checkpoint, a surveillance mechanism ensures accurate chromosome segregation by facilitating the assembly of the mitotic checkpoint complex and promoting its binding to the anaphase-promoting complex/cyclosome. Although BubR1s role in SAC signaling has been extensively investigated, the function of its N-terminal tetratricopeptide repeat (TPR) domain remains poorly understood. In this study, we first established the essential role of the BubR1 TPR domain in SAC signaling. Guided by the resolved cryo-EM structure of the MCC-APC/C complex, we identified and characterized several interactions involving this domain with Mad2, Cdc20APC/C, Apc2. Furthermore, we discovered an intramolecular interaction between the TPR domain and downstream residues of BubR1, which appears to organize a structure resembling a "lasso" that incorporates four Cdc20APC/C-binding elements, thereby enhancing engagement with Cdc20 in the APC/C. Functional and biochemical analyses demonstrated that these interactions collectively promote MCC assembly and MCC-APC/C binding, enabling rapid SAC activation in response to microtubule-kinetochore attachment defects.

cell biology↗

bioRxiv2025

DeepCEF: A Deep Causal Estimation Framework for Complex Biological Systems Integrating Local Scores, Independence Tests, and Relation Attributes

Causal relationship identification is a fundamental and complex research challenge that spans multiple disciplines, including biology, epidemiology, economics, and philosophy. Various scoring techniques and independence tests, such as local scores (e.g., Degenerate Gaussian (DG) and Bayesian Information Criterion (BIC)) and independence tests (e.g., Fishers Z), have been employed in causality estimation. However, these local scores often excel in specific data types or application areas but falter in others, limiting their ability to capture the complexity and heterogeneity of underlying causal mechanisms. For instance, a method may perform well on linear relationships or continuous variables but struggle with discrete variables or non-linear relationships. Real-world observational datasets, particularly those generated in complex biological systems, often contain diverse data types and relationships, making it essential to develop a more comprehensive approach. To address this challenge, we propose a novel causal estimation framework that leverages the powerful classification capabilities of deep neural networks (DNNs) to identify causal patterns in pairwise relationships. Our framework integrates multiple local causality estimation scores, independence tests, and variable attributes, allowing it to capture a wide range of causal mechanisms. To ensure the frameworks robustness and generalizability, we incorporate a diverse range of simulation data and 10 curated real-world datasets into the training procedure. Furthermore, our framework is designed to be extensible, enabling users to easily integrate their own data and additional scores and tests. Our validation results demonstrate that our framework outperforms existing methods in terms of estimation accuracy and precision on both simulation data and real-world biological datasets. By providing a more comprehensive and adaptable approach to causal relationship identification, our framework has the potential to advance research in various fields and improve our understanding of complex biological systems.

bioinformatics↗

bioRxiv2025

Macrophages display spatiotemporal specificity in intrahepatic cholangiocarcinoma and drive tumour progression via OSM and THBS1

Tumor-associated macrophages (TAMs) are abundant in intrahepatic cholangiocarcinoma (ICC) and correlate with poor prognosis, but their non-immunosuppressive roles remain unclear. This study aimed to define TAM transcriptional heterogeneity and map their interactions with ICC cells that promote malignancy beyond immune suppression. Single-cell and spatial transcriptome analysis with mouse and human ICC tissues revealed a TAM subpopulation, designated M{varphi}_VEGFA, that emerged as the major macrophage population from the intermediate stage of ICC development onward. Data from Gene Expression Omnibus (GEO) and spatial transcriptome indicate that M{varphi}_VEGFA was associated with poor prognosis and spatially localized to the ICC cells. Cell co-culture and cell-cell communication analyses revealed that M{varphi}_VEGFA promoted ICC cell proliferation via secreted OSM and downstream OSMR-STAT3-CCND1 axis, and enhanced ICC cell invasion through THBS1 and downstream CD47-mTOR/DBN1 signaling. Critically, multiplex immunofluorescence with human ICC tissue microarray indicated that OSM and THBS1 were co-elevated in human ICCs, and dual blockade of both targets inhibited ICC progression in mouse models. This study uncovers the direct and critical roles of M{varphi}_VEGFA in driving ICC progression with paracrine signaling and further highlights the potential of targeting macrophages in ICC treatment.

cancer biology↗

bioRxiv2025

Acidic transcription factors position the genome at nuclear speckles through transcription dependent and independent mechanisms

A small fraction of the genome positions reproducibly near nuclear speckles (NS), increasing expression and/or splicing efficiency of NS-associated genes. How specific genomic regions target to NS remains unclear. Here, we demonstrate that establishment of genome-wide NS-association occurs independent of active transcription. We show that DNA sequences derived from NS-associated regions integrated as transgenes autonomously target to NS. By systematically dissecting one such genomic locus, the COL1A1-SGCA locus, we identified redundant NS-targeting cis regulatory elements, including a [~]600 bp fragment with 17 binding motifs for 8 transcription factors (TFs). Four NS-targeting TFs within this fragment contain acidic activation domains (AADs) that provide both chromatin-context and transcription-dependent NS-targeting, a property that appears common among several other tested AADs. A subset of acidic activator TFs contain an additional, transcription-independent NS-targeting activity. Our findings establish diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at NS periphery for context-specific transcriptional responses.

cell biology↗

bioRxiv2025

From Correlation to Causation: Cell-Type-Specific Gene Regulatory Networks in Alzheimer's Disease

INTRODUCTIONAlzheimers disease (AD) involves complex regulatory disruptions across multiple brain cell types, yet a comprehensive understanding of the intracellular causal mechanisms remains unclear. METHODSWe presented an integrative analysis framework using single-nucleus transcriptomic with matched subject-level genotype data from 272 human AD in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) study, and constructed causality-based, cell-type-specific gene regulatory networks (GRNs). RESULTSOur method identifies regulatory genes from both transcription factors (TFs) and non-TFs, thereby capturing a complete and accurate causal regulatory map across different brain cell types. This work revealed both established and novel regulations, pathways, and cell-type-unique hub genes in AD. Beyond constructing transcriptome-wide GRNs, we quantitatively assessed hub genes and distinguished those with regulatory or responsive roles. DISCUSSIONOur study provides a comprehensive mapping of cell-type-specific causal GRNs in AD, providing a powerful resource for dynamic pathway exploration, hypothesis generation, and functional interpretation.

neuroscience↗

bioRxiv2025

Effects of the Neutral CB1 Receptor Antagonist AM6527 on Spontaneous, Consummatory, and Motivated Behavior in Mice

RationaleThe cannabinoid type-1 receptor (CB1R) signaling pathway plays a central role in regulating motivational and feeding behaviors. Neutral CB1R antagonists represent a promising therapeutic class with potentially fewer adverse effects than inverse agonists, yet their behavioral effects remain incompletely characterized. ObjectivesWe investigated the behavioral profile of AM6527, orally bioavailable neutral CB1R antagonist, across naturalistic and operant paradigms in male mice. To evaluate dopaminergic involvement in AM6527s effects, we employed several pharmacological interventions. ResultsUsing machine learning-based Motion-Sequencing (MoSeq), which parses spontaneous behavior into sub-second syllables, we found that AM6527 did not affect overall speed in an open field, however, it increased the self-directed behaviors and reduced specific locomotor syllables at the highest dose tested. In a naturalistic reward consumption paradigm, AM6527 produced a dose-dependent reduction in milk intake. Operant conditioning paradigms revealed robust suppression of motivated responding on fixed ratio-3 and progressive ratio (PR) schedules for palatable milk reward, with the greatest impact on high-baseline performers under PR conditions. To understand the dopaminergic involvement, we co-administered dopaminergic drugs (targeting D1R, D2R, or dopamine transporter) which resulted in partial rescue of operant responding, indicating dopaminergic and non-dopaminergic contributions to AM6527s observed behavioral effects. ConclusionOur findings suggest that neutral CB1R antagonism suppresses consummatory and motivated behaviors via dopamine-dependent and -independent mechanisms. By leveraging sub-second behavioral analysis with MoSeq, we further reveal distinct changes in spontaneous behavior, underscoring the relevance of CB-based treatments for maladaptive appetitive and motivational states in both psychiatric and metabolic disorder.

neuroscience↗

bioRxiv2025

Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle

AMPK (5'-AMP-activated protein kinase) is an energetic sensor for metabolic regulation and integration. Here, we employed CRISPR/Cas9 to generate non-activatable Ampk knock-in (KI) mice with mutation of threonine 172 phosphorylation site to alanine, circumventing the limitations of previous genetic interventions that disrupt the protein stoichiometry. KI mice of Ampk2, but not Ampk1, demonstrated phenotypic changes with increased fat-to-lean mass, impaired endurance exercise capacity, and diminished mitochondrial maximal respiration and conductance in skeletal muscle. Integrated temporal multi-omic analysis (proteomics/phosphoproteomics/metabolomics) in skeletal muscle at rest and during exercise establishes a pleiotropic yet imperative role of Ampk2 T172 activation for glycolytic and oxidative metabolism, mitochondrial respiration, and contractile function. Importantly, there is a significant overlap of skeletal muscle proteomic changes in Ampk2 T172A KI mice with that of type 2 diabetic patients. Our findings suggest that Ampk2 T172 activation is critical for exercise performance and energy transduction in skeletal muscle and may serve as a therapeutic target for type 2 diabetes.

molecular biology↗

bioRxiv2025

Modeling Fibrosis with MASH Patient Liver-Derived Organoids.

Metabolic dysfunction-associated steatohepatitis (MASH) can lead to liver fibrosis and cirrhosis ultimately leading to liver transplantation or death. Therapeutic options for MASH-associated fibrosis are limited in part because of the lack of good model systems. To address this challenge, we developed a 3D MASH liver fibrosis model by using organoids derived from MASH patient liver co-cultured with human liver-derived hepatic stellate cells (HSC) and human peripheral blood monocytes (MC). Spontaneous self-assembly resulted in fibrotic scar-like 3D structures with senescent parenchymal cells, proliferating collagen secreting myofibroblasts (MFB) and proinflammatory TREM2+ scar-associated macrophages (MP). Single cell RNA sequencing suggested high similarity with MASH patient liver fibrotic scars. Lipid nanoparticles (LNPs) formulated with anti-YAP1siRNA could specifically and efficiently knockdown YAP1 in the MFBs, resulting in MFB senescence, a desirable therapeutic goal. This MASH patient liver-derived fibrosis model opens novel avenues towards testing treatments for MASH-associated liver fibrosis with reduced adverse effects.

bioengineering↗

bioRxiv2025

The Genetic Immune Basis of Gout: Identification, Functional Characterization, and Therapeutic Implications

Gout, the most common inflammatory arthritis, is still managed mainly as a metabolic disorder, with treatment centered around urate lowering rather than blocking the immune response that drives gout flares. This emphasis reflects a historical view of gout as a disease of excess and diet, reinforced by genome-wide association studies (GWAS) that consistently detect urate transport and metabolism loci, while immune-related loci have failed to reach genome-wide significance. Growing clinical and experimental evidence, however, points to a central role for immune pathways in gout pathogenesis. We set out isolate the immune genetic component of gout. Using a conjunctional false discovery rate (conjFDR) framework, we integrated gout GWAS data with those from eight immune-mediated disorders rheumatoid arthritis, Crohns disease, inflammatory bowel disease, psoriasis, multiple sclerosis, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. We observed robust pleiotropic enrichment across all comparisons and mapped the resulting loci through FUMA to 85 unique credible genes broadly distributed across the genome, with no classical urate transporters present. Additionally, we identified 16 novel genes for gout, many of which are of obvious immune nature. We performed GO and KEGG enrichment analyses, which at a stringent q-value threshold identified adaptive and innate immune pathways, including T and B cell receptor signaling, antigen processing and presentation, NF-{kappa}B signaling, and Jak-STAT signaling. At a nominal p-value threshold, we uncovered additional cytokine-driven processes such as IL6 and IL7 signaling. We confirmed disease relevance with DisGeNET and established causality for 14 genes through Mendelian randomization, including IL1RN, MAP3K11, and SH2B3 genes with existing pharmacological inhibitors. We are the first to genetically isolate the genetic immune component of gout. Our findings show that these immune pathways can be specifically targeted, and immune medication should be incorporated into therapeutic strategies to complement urate-lowering approaches.

immunology↗

bioRxiv2025

Stepwise emergence of recombination suppression precedes fissiparous asexuality in the planarian Schmidtea mediterranea

A central paradox in evolutionary biology is the rarity of asexual reproduction, which is often attributed to developmental constraints and long-term costs. Yet, fissiparous asexuality--where animals split and regenerate--is widespread among planarians, hinting at genomic features predisposing them to asexuality. We investigated the genomic underpinnings and evolutionary consequences of asexuality in the planarian Schmidtea mediterranea, which exists as both obligately fissiparous and sexual strains. We generated a haplotype-phased genome assembly of the asexual strain and collected population genomic data from laboratory and wild populations to uncover extensive heterozygous chromosomal rearrangements affecting all chromosomes. We show that these rearrangements arose in a sexually reproducing ancestor without directly disrupting reproductive genes but instead progressively suppressing recombination across the genome. The asexual genome exhibits minimal deleterious mutation accumulation, indicating a low cost of asexuality. Population-genomic data show this strain lacks any detectable sexual reproduction and originated recently (0.17-0.4 Ma), but the young age is insufficient to explain the low mutational burden. Instead, planarians may be able to exploit the lack of a single-cell bottleneck in fissiparous reproduction to mitigate the costs of asexuality. Altogether, our results support a model in which stepwise recombination suppression due to structural rearrangements eroded the benefits of sex and enabled the emergence of fissiparous asexuality in S. mediterranea.

evolutionary biology↗

bioRxiv2025

DNA Data Storage Architecture via Ligation of Dynamic DNA Bytes

The explosive growth of digital data is overwhelming conventional storage media, creating an urgent need for more efficient solutions. DNA offers immense potential for digital data storage, yet most systems remain static and archival. Here, we present a modular DNA storage architecture based on dynamic DNA bytes (DynaBytes)-- pre-fabricated DNA segments that can be ligated into reconfigurable information units. Utilizing core, functional and control DynaBytes, we stored 210,776 bits (26,347 bytes) of digital information organized within a file-system, and demonstrated CRUD (Create-Read-Update-Delete)-like operations, hierarchical access and nanopore-based realtime retrieval. Robust data recovery was achieved under [~]100x error-prone sequencing using streamlined error correction and fuzzy decoding. By relying on in vitro ligation of standardized components, DynaBytes reduces cost, scales efficiently, and allows interactive, rewritable storage. These features advance DNA storage beyond passive archiving toward a reconfigurable framework, opening new possibilities for dynamic, practical and large-scale DNA-based data systems.

synthetic biology↗

bioRxiv2025

Experimenting with Two Recent Feature Selection Methods for High-Dimensional Biological Data

Feature selection in high-dimensional biological data, where the number of features far exceeds the number of samples, has long posed a significant methodological challenge. This study evaluates two recently developed feature selection methods, Stabl and Nullstrap, under a simulation framework designed to replicate regression, classification, and non-linear regression tasks across varying feature dimensions and noise levels. Our results demonstrate that Nullstrap consistently outperforms Stabl and other benchmarked methods across all evaluated scenarios. Furthermore, Nullstrap proved significantly faster and more scalable in high-dimensional settings, underscoring its suitability for large-scale omics data applications. These findings establish Nullstrap as a robust, accurate, and computationally efficient feature selection tool for modern omics data analysis.

bioinformatics↗

bioRxiv2025

Multiomic profiling reveals pericyte and smooth muscle cell contributions to CADASIL pathology in cell-specific Notch3 mutant mice

Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial SVD. CADASIL is caused by dominant missense mutations in Notch3, a receptor expressed in mural cells, including smooth muscle cells (SMCs) and pericytes. However, the cell-type specific contributions driving the CADASIL pathology remain unknown due to lack of animal models. Here, we generated two conditional knock-in mouse models carrying the CADASIL-causing Notch3R170C mutation selectively in SMC and brain pericytes. Both Notch3R170Cmodels showed perivascular accumulation of the NOTCH3 extracellular domain, yet developed distinct neurovascular changes depending on the affected cell type. Pericyte-specific Notch3R170C mice displayed pronounced region-selective microglial activation and vascular changes, whereas SMC-specific Notch3R170C mice showed localized perivascular gliosis with minimal vascular remodeling. Proteomic profiling of isolated brain vessels revealed largely unique cell-specific responses. Pericytes Notch3R170C expression dysregulated metabolic pathways, whereas SMC Notch3R170C expression induced immune signaling related pathways. Integration with single-cell RNA-seq data revealed that many of the proteomic and phosphoproteomic shifts might also include brain endothelial cells, including metabolic changes in the presence of pericyte Notch3R170C and inflammatory signaling in the presence of SMC-Notch3R170C. Together, these findings define mural cell-specific mechanisms that contribute to the CADASIL-associated vascular pathology.

neuroscience↗

bioRxiv2025

Visible Light-Controllable Surgical Hemostatic Adhesives Enabled by Vitamin B12-Stabilized Poly(α-Lipoic Acid)

Water-resistant adhesives are indispensable for biomedical applications, from surgical wound closure to internal hemostasis. While poly(-lipoic acid)-based adhesives show promise for their strong underwater adhesion, their clinical utility has been limited by uncontrolled polymerization-depolymerization dynamics. Here we present a visible light-controllable adhesive system enabled by a simple mix of -lipoic acid (LA) and vitamin B12 (i.e., adenosylcobalamin or AdoB12)--a photolabile compound--without resorting to any chemical modification. Benign visible light irradiation facilitates the cleavage of the C-Co bond and the subsequent formation of B12-thiolate complexes that stabilize LA polymers against depolymerization. The photoresponsive LA-AdoB12 adhesive system has proven highly effective in a wide range of surgical applications, achieving (1) strong bonding in porcine skin models in vitro, (2) reliable sealing of punctured organs (lung, heart and stomach) ex vivo, and (3) immediate hemostasis in active bleeding models such as topical, esophageal, and intestinal wounds in vivo. This work highlights a simple yet powerful strategy for creating visible light-controllable bioglues well-suited for diverse surgical applications.

bioengineering↗

bioRxiv2025

Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation

IDH-wildtype grade IV glioblastoma is the most aggressive adult primary brain tumor and remains refractory to anti-PD-1 monotherapy despite evidence of limited tumor-specific T cell induction. To determine the impact of immune checkpoint inhibitors (ICIs) on glioblastoma T cell transcriptional landscape and repertoire, we conducted paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) of tumor-infiltrating lymphocytes (TILs) from patients with untreated, newly diagnosed glioblastoma and from recurrent glioblastoma treated with dual checkpoint blockade targeting PD-1 and LAG-3. Using a validated transcriptional signature, we found that predicted tumor-reactive T cells (TRC) in untreated glioblastomas reside almost exclusively in a clonally expanded GZMKhi population with developmental plasticity, affording them the potential to differentiate into both tissue-resident and terminal effector T cells. Dual ICI therapy induced substantial clonal remodeling, characterized by the recruitment of new TRC from the periphery into the tumor microenvironment (TME) and differentiation into transitional effectors and ultimately terminal effectors along a gradient characterized by simultaneous acquisition of cytotoxic and exhaustion genes, regulated by specific transcriptional, metabolic, and epigenetic programs. Longitudinal clonal tracking in peripheral blood confirmed that with ICI treatment, most TRC expand transiently in circulation prior to tumor infiltration, with peripherally derived clones becoming the major contributor to the GZMKhi TRC that further expand in the tumor. Our study provides the first comprehensive map of T cell clonal dynamics and differentiation in glioblastoma following dual ICIs and highlights a potential mechanism of immune activation and peripheral recruitment of TRC in glioblastoma not previously described. Our results suggest that therapeutic strategies to sustain these GZMKhi early effector and transitional effector T cells may further enhance ICI therapeutic efficacy in glioblastoma.

immunology↗

bioRxiv2025

Human-specific features of the cerebellum and ZP2-regulated synapse development

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

neuroscience↗