Cell reports最新文献

Neuro-glial mitochondrial transfer critically sustains neuronal function in disease. While this transfer reshapes inflammatory microenvironments, its pathological mechanisms in peripheral inflammatory pain remain uncharacterized, impeding targeted interventions. Here, employing primary satellite glial cells (SGCs)-trigeminal ganglion neurons (TGNs) co-culture models, we demonstrate that, during acute inflammation, SGCs transfer functional mitochondria to injured TGNs via tunneling nanotubes and free mitochondrial uptake. Inflammatory stress impairs mitophagy, leading to dysfunctional mitochondrial accumulation and heightened neuronal hyperexcitability. Mitochondria from SGCs restore mitophagic flux and enhance mitochondrial-endoplasmic reticulum (ER) contact sites, thereby facilitating calcium exchange and homeostasis while reducing neuronal hyperexcitability. Critically, Atl1 knockout and overexpression mice models reveal that ATL1-driven ER restructuring initiates autophagosome formation during mitophagy and regulates early-stage autophagic progression. Taken together, our findings uncover a neuroprotective axis wherein glial mitochondrial donation safeguards neurons, directly nominating mitochondrial dynamics for therapeutic intervention in orofacial inflammatory pain.

RIG-I (DDX58) is typically localized in the cytoplasm and activates innate immunity. However, the mechanisms governing its nuclear translocation and functions remain incompletely understood. Here, we discover that RIG-I undergoes lactylation, which is mediated by the acetyltransferase PCAF. Treatment with the lactate transporter inhibitor syrosingopine blocks the efflux of lactate from cancer cells, increasing intracellular lactate concentration, promoting RIG-I lactylation, and enhancing the nuclear translocation of lactylated RIG-I in an importin 8-dependent manner. The nuclear-localized RIG-I interacts with PARP1 and attenuates its activity, thereby inhibiting DNA damage repair. Moreover, we find that low RIG-I expression is associated with unfavorable prognosis and survival in lung adenocarcinoma (LUAD). Syrosingopine treatment sensitizes LUAD cells to PARP inhibitor (PARPi) and potentiates the therapeutic efficacy of olaparib in a mouse LUAD model. Altogether, our study reveals that lactylation drives RIG-I nuclear function to inhibit DNA damage repair via PARP suppression. This supports the potential co-administration of syrosingopine and PARPi for LUAD treatment.

Dorsal root ganglia (DRG) somatosensory neurons of the mechano/proprioceptive and thermo/nociceptive lineages differentiate during successive neurogenic waves defined by the complementary expression and combinatorial roles of the proneural genes Neurog2 and Neurog1. Using a gene-swapping approach, we show here that both paralogs are largely interchangeable in this structure and beyond, including for fate determination, indicating that their specific requirements primarily reflect divergent evolution of their regulatory sequences rather than protein activities. This result, combined with birth-dating data and phenotyping of complementary transgenic models, where delayed onset or premature arrest of neurogenesis predictably triggers opposite changes in DRG content, highlights that somatosensory precursors' commitment to the mechano/proprioceptive or thermo/nociceptive lineage is rapidly biased but critically depends on differentiation timing. Together, these findings support a model where the dynamic spatiotemporal expression of functionally equivalent Neurog1 and Neurog2 proteins ensures a protracted neurogenic period, allowing the sequential emergence of distinct neuronal lineages.

Pancreatic ductal adenocarcinoma is heterogeneous, with low tumor purity, a prominent microenvironment, and complex architecture, which preclude the identification of shared tumor-intrinsic and stromal biology within and across patients. We overcame these challenges by achieving necessary resolution and context through the application of complementary genomics, pathology, and machine-learning approaches to characterize primary untreated tumors from 39 patients. We captured 340,000 spatial low-bulk and 530,000 spatial single-cell transcriptomes and observed a spectrum of classical-to-basal tumor subtypes present within all patients. We found that each subtype has distinct regulators, stromal neighborhoods, microenvironment, extracellular matrix, and histology corresponding to multiple immunosuppressive and therapy resistance mechanisms. We defined key tumor heterogeneity features, including the presence of mixed KRAS mutations and tertiary lymphoid structures, identifying biomarkers that distinguish the latter from lymph nodes. Lastly, by leveraging patient, cell, and mouse data, we determined which aspects of tumor biology are recapitulated in bulk datasets and reductionist models.

Antagonistic interactions between center and surround regions of the receptive field are widely observed across sensory systems. In the early visual system, these interactions contribute to important computations such as edge detection. However, less is known about how center-surround interactions depend on the spatiotemporal properties of the visual input. Here, we show that surround motion strongly modulates the response properties of two understudied primate ganglion cell types. Broad thorny cell responses are strongest when motion in the center and surround is uncorrelated, similar to object-motion-sensitive cells found in other species. A different pattern is observed in On smooth monostratified cells: surround activation is suppressive for static stimuli and facilitatory for motion. These effects of surround activation diverge significantly from classical center-surround models and more closely resemble how surround motion affects responses in primate visual cortex.

Transposable elements (TEs) reshape mammalian cis-regulatory landscapes, but the mechanisms controlling their context-specific activity remain unclear. KRAB zinc finger proteins (KZFPs) typically repress TE-derived regulatory activity via TRIM28-mediated H3K9me3 deposition. We expand this paradigm by uncovering non-canonical KZFP-TE relationships. Through comprehensive epigenomic mapping of KZFP-bound TEs, we show that ancient mammalian L2/MIR elements' regulatory activity is delineated by KZFP binding despite low H3K9me3 enrichment. We dissect this relationship by focusing on ZNF436, a non-canonical KZFP highly expressed in the developing human heart. We find that ZNF436 preserves cardiomyocyte function by promoting cardiac gene expression while restricting alternative lineage programs. Mechanistically, ZNF436 associates with the SWI/SNF remodeling complex to limit the accessibility of L2/MIR-derived CREs, otherwise active in non-cardiac tissues. Our findings reveal a TRIM28-independent role for KZFPs in shaping cell-type-specific regulatory landscapes and emphasize the importance of repressing alternative lineage programs while activating lineage-specific ones to safeguard cell identity.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome characterized by neurofibromas, Nf1^-/- Schwann cell (SC)-derived tumors of peripheral nerves. We and others have shown that Nf1 loss in SCs is insufficient for neurofibroma formation but cooperates with an injury microenvironment to form tumors, but the mechanisms remain unknown. Here, we identify TGF-β as the microenvironmental injury signal that is essential for tumorigenesis. Analysis of the earliest stages of neurofibroma formation showed that tumor formation is associated with a population of Nf1^-/- SCs that "escape" the regenerating nerve shortly after injury. Here, they reside in a distinct microenvironment conducive to tumorigenesis, where TGF-β disrupts SC/axonal interactions and SC re-differentiation. Pharmacological inhibition of TGF-β for a short therapeutic window during this early stage inhibited tumor formation, highlighting the potential to normalize Nf1^-/- SCs and identifying TGF-β as a potential therapeutic target to both treat and prevent neurofibroma formation.

Distinct epithelial cell states arise during differentiation, but mechanisms generating transcriptomic diversity among them remain poorly defined. The human ureter urothelium contains basal progenitor, intermediate cells, and terminally differentiated umbrella cells. Prior single-cell RNA sequencing revealed similar global gene expression profiles across these states, raising the question of how distinct identities emerge. Here, we show that alternative cleavage and polyadenylation (APA) introduces a major layer of transcriptomic diversity during urothelial differentiation, largely independent of changes in mRNA levels. Analysis of 13,544 urothelial cells identified hundreds of differentiation-associated APA events. Single-cell imaging revealed spatially specific APA patterns, and reporter assays demonstrated gene- and context-dependent control of protein expression by alternative 3' untranslated regions (3' UTRs), consistent with in situ protein patterns. Conserved motifs in APA-regulated 3' UTRs, including transcription factor binding sites and Alu elements, suggest mechanisms for polyadenylation site selection. Our study establishes APA as a key contributor to transcriptomic complexity in the human urothelium.

How the brain combines information received independently by the two hemispheres is not fully understood. Here, we describe a non-reciprocal circuit for interhemispheric communication in the mouse binocular visual cortex via anatomically segregated neuronal populations. Callosal projecting neurons (CPNs) receive only weak or no callosal input, whereas callosal receiving neurons (CRNs) make only weak or no callosal projections. Both populations receive direct input from the thalamus. At the cellular level, CRNs have reduced excitability compared to non-CRNs (putative CPNs) due to higher Kv1 potassium channel expression (encoded by the KCNA2 gene), with excitability of CRNs correlating with the magnitude of callosal input. Functionally, CRNs are predominantly binocular, with binocularity correlating with callosal input, whereas non-CRNs (putative CPNs) are predominantly monocular. In summary, we find that non-reciprocal callosal projections between CPNs and CRNs together with differences in excitability shaped by callosal input underlie interhemispheric communication in binocular visual cortex.

A central goal of population genomics is to unveil the evolutionary forces driving genomic divergence. Although genomic islands have been extensively studied in angiosperms, the patterns of genomic divergence remain poorly understood in gymnosperms. Here, by re-sequencing the whole genome of 130 individuals of Welwitschia mirabilis, we reveal significant genomic differentiation among its geographically close populations. Population genomic analyses suggest that geographical isolation and species characteristics play important roles in triggering and maintaining population divergence. We also identify multiple genomic islands of elevated divergence, which are primarily attributed to divergent sorting of ancient polymorphisms and divergence hitchhiking. Further genome-wide association analyses indicate that Welwitschia has an XY-type sex-determination system, with the sex-linked region located at 72.04-92.82 Mb on chromosome 6. Our findings are important for comprehending the evolutionary forces shaping genomic patterns of differentiation and the genetic basis of sex determination in gymnosperms.