Cell reports最新文献

Multipolar migration is a conserved neuronal migration mode in the developing brain, enabling emerging neurons to navigate in crowded environments and reach precise laminar positions. Yet, how these cells interpret external cues to guide their migration is not fully understood. We investigate this question using retinal horizontal cells as a model. Combining transcriptomics, targeted CRISPR screening, and live imaging, we reveal the spatiotemporal guidance system underlying horizontal cell lamination: repulsive Slit1b/2-Robo2 signaling in the amacrine cell layer initiates apical horizontal cell migration, while attractive neurturin-Gfrα1/2 signaling from photoreceptors fine-tunes final positioning beneath the photoreceptor layer. Disruption of these pathways causes basal retention of horizontal cells, highlighting the importance of spatially coordinated signaling for proper lamination and functional retinal circuitry. Our results uncover how positional signals and tissue architecture cooperate to achieve neuronal migration precision, a principle likely relevant across the developing central nervous system.

Animals reprioritize behavioral goals in response to internal physiological states. Using larval zebrafish, we investigated whether engagement with a visuomotor task, the optomotor response (OMR), is coupled to cardiac dynamics. We discovered that threats lead to tachycardia that is synchronized with behavioral suppression. The change in heart rate is represented in the activity of specific neuronal populations. Severing the input to the sympathetic ganglia or ablating the vagus nerve revealed that the threat-related changes to behavioral state do not require interoceptive pathways. Direct tachycardic optopacing of the heart similarly suppressed the OMR response, but by reducing cardiac filling during diastole, thereby impacting oxygen delivery to the CNS. Optopacing also changed the activity of specific brain regions but in neurons distinct from those associated with threat-induced tachycardia. These cardiac function-associated central changes may have relevance to autonomic imbalances in anxiety, stress, and orthostatic disorders.

Root-knot nematodes cause substantial crop losses by compromising plant immunity and facilitating invasion by soil-borne bacterial pathogens, yet the mechanisms underlying nematode-facilitated co-infection remain poorly understood. Here, we quantify the global prevalence of nematode-pathogen co-infection and integrate multi-omic analyses across greenhouse and in vitro experiments. We show that nematode invasion activates plant defense gene expression but concurrently disrupts rhizosphere homeostasis, resulting in microbiome dysbiosis that overrides host resistance. Meloidogyne invasion induces pronounced metabolic reprogramming, characterized by depletion of tomatidine and accumulation of carbohydrate metabolites such as galactose. These shifts selectively suppress Streptomyces-dominated antagonistic microbiota while enriching Acidovorax, which exhibits nutritional synergy with Ralstonia. Using synthetic microbial community transplantation, we demonstrate a functional transition from pathogen-suppressive to pathogen-permissive bacteriomes following nematode invasion. Together, our findings reveal how nematodes and bacterial pathogens cooperatively subvert plant-microbe metabolic signaling to undermine rhizosphere immunity, highlighting actionable targets for microbiome-based disease control.

Emerging evidence has highlighted lactylation as a critical link between metabolism and tumor progression. Through integrative lactylome and proteome profiling, we delineate the global landscape of protein lysine lactylation in bladder cancer, identifying lysine (K)47 and K50 of Rho guanosine diphosphate dissociation inhibitor β (ARHGDIB) as lactylation sites. Histone deacetylase (HDAC)2-mediated delactylation abrogates the tumor-suppressive function of ARHGDIB, promoting metastasis and cisplatin resistance of bladder cancer. Mechanistically, delactylation of ARHGDIB attenuates its binding affinity for Rac1, facilitating Rac1 membrane translocation and activation. This enhances DNA damage repair through the Rac1-MRN-ATM-CHK2 axis. Clinically, reduced ARHGDIB-K50 lactylation levels correlate with cisplatin resistance and poor prognosis. Entinostat, an inhibitor of class I HDAC, synergizes with cisplatin by preventing ARHGDIB delactylation. Collectively, our findings unveil a unique paradigm in which delactylation of tumor suppressors drives metastasis and chemoresistance. Targeting lactylation dynamics with HDAC inhibitors presents an avenue for intervention of bladder cancer.

Understanding the function of genetic variants associated with human traits and diseases remains a significant challenge. Here, we combined analyses based on natural genetic variation and genetic engineering to dissect the function of 94 non-coding variants associated with hematological traits. We describe 22 genetic variants impacting hematological variation through gene expression. Further, through in-depth functional analysis, we illustrate how a rare, non-coding variant near the CUX1 transcription factor impacts megakaryopoiesis through the modulation of the CUX1 transcriptional cascade. Collectively, our findings enhance the functional interpretation of genetic association studies and advance understanding of how non-coding variants contribute to blood and immune system variation.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease of the central nervous system (CNS) that, despite overlapping phenotypic features with multiple sclerosis (MS), manifests with more severe clinical outcomes. The defining pathogenic driver of NMOSD is the aquaporin-4 (AQP4) autoantibody, which induces astrocytic injury via complement-dependent cytotoxicity (CDC). MS is predominantly managed with disease-modifying therapies (DMTs) such as interferon-beta (IFN-β) to reduce relapse rates. However, these therapies are often ineffective or even detrimental in NMOSD. Our findings demonstrate that while IFN-β mitigates experimental autoimmune encephalomyelitis (EAE), it exacerbates NMOSD-like astrocytopathy. Deleting IFNAR1 counteracts this effect by selectively enhancing astrocyte activation without altering other CNS cells. Subsequently, we characterized multiple MS therapeutics that paradoxically worsen NMOSD-like pathology, whereas agents promoting astrocytic activation confer protection. Collectively, we establish a framework for astrocyte-centered drug screening and underscore the therapeutic potential of targeting astrocytes in NMOSD, connecting fundamental disease mechanisms to clinical applications.

Studies have demonstrated that repeated mRNA vaccination enhances the breadth of neutralization against diverse severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. However, the development of antibodies capable of neutralizing across the Coronavirinae subfamily is poorly understood. In this study, we analyze serum samples to determine their neutralization breadth and potency and identify their antigenic targets. Using a cohort of older individuals and healthcare workers, we track correlates of broad neutralizing responses, including fusion peptide (FP) antibody elicitation. We find that although broadly neutralizing responses are often a result of receptor-binding domain (RBD)-specific antibodies, a rare subset of donors produce FP-specific broadly neutralizing responses. Interestingly, FP-specific antibodies are not observed in COVID-naive individuals, irrespective of vaccination regimen; rather, they occur following natural infection or vaccine breakthrough. This study highlights which epitope targets underpin broadly neutralizing antibody responses to coronaviruses and suggests that existing vaccines are insufficient to promote the elicitation of FP-directed broadly neutralizing coronavirus antibodies.

Mutations in the pioneer transcription factor FOXA1 occur in 10%-40% of prostate cancers and broadly alter chromatin accessibility. In a cohort of 874 primary and metastatic tumors, we confirm frequent Wing2 missense mutations and indels, as well as C-terminal truncating frameshifts. To define their functional impact, we performed single-nucleus multiome profiling in mouse prostate organoids expressing representative alleles, including overexpressed wild-type FOXA1. Each subgroup produces distinct chromatin and transcriptional changes, but all perturb epithelial lineage specification. Indel mutants promote basal-like states, whereas C-terminal truncations, Wing2 missense mutations, and elevated wild-type FOXA1 drive secretory L1-like luminal fates. Integrated RNA-seq, ATAC-seq, and ChIP-seq reveal that L1-like specification involves a hybrid androgen receptor/FOXA1 motif and cooperation with POU2F1. In vivo, these same alleles, combined with Trp53/Pten loss, shift tumor histology from basal-like to secretory luminal phenotypes.

Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC) and occur via an ascending route. UPEC invades bladder epithelial cells, causing cystitis and ascends to the kidneys, inducing pyelonephritis. Flagella-mediated motility is critical for this dissemination. The fliLMNOPQR operon encodes essential flagellar components, which are required for flagellar motility. However, the regulatory mechanisms that activate the expression of flagellar genes, facilitating bacterial motility in response to host cues, remain unclear. This study reported that the two-component system HprSR directly activates fliLMNOPQR expression, promoting UPEC kidney colonization in response to host-derived reactive oxygen species (ROS) and reactive chlorine species (RCS). The hprSR mutation impairs UPEC kidney colonization due to reduced expression of flagellar genes. Neutralization of ROS and RCS in the mouse urinary tract prevents kidney colonization by inactivating HprSR. This study reveals a regulatory pathway in which host-derived signals activate UPEC virulence to mediate kidney colonization.

Prosocial behaviors, such as rescuing individuals in need, are crucial for social cohesion across species. While key brain regions involved in rescue behavior have been identified, the underlying neural mechanisms remain unclear. The hippocampus (HPC), known for its role in memory and spatial navigation, also contributes to emotional and social processing. However, its specific involvement in prosocial behavior is not well understood. Here, we investigate the causal role of the HPC in learning and executing rescue behavior in mice. Using chemogenetics, we show that the dorsal HPC (dHPC), but not the ventral HPC (vHPC), is essential for acquiring rescue behavior. Calcium imaging of the dHPC reveals network consolidation during successful rescues, with distinct synchronized ensembles and activity patterns linked to the liberation of an individual in need. These findings establish a previously unrecognized role for the dHPC in prosocial behavior, providing insights into the neural mechanisms underlying empathy-driven actions.