EMBO Reports最新文献

During ovariogenesis, more than two-thirds of germ cells are sacrificed to improve the quality of the remaining oocytes. However, the detailed mechanisms behind this selection process are not fully understood in mammals. Here, we developed a high-resolution, four-dimensional ovariogenesis imaging system to track the progression of oocyte fate determination in live mouse ovaries. Through this, we identified a cyst-independent oocyte phagocytosis mechanism that plays a key role in determining oocyte survival. We found that oocytes act as individual cells, rather than connected cyst structures, during ovarian reserve construction. In this process, dominant oocytes capture and absorb cell debris from sacrificed oocytes to enrich their cytoplasm and support their survival. Single-cell sequencing indicated that the sacrificed oocytes are regulated by autophagy. When oocyte sacrifice was inhibited using autophagy inhibitors, the pool of surviving oocytes expanded, but they failed to fully develop and contribute to fertility. Our study suggests that mammals have evolved a cyst-independent selection system to improve oocyte quality, which is essential for sustaining a long reproductive lifespan.

The brain's perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how activity-induced synaptic plasticity is achieved in the adult brain with a dense ECM is unclear. We hypothesized that neuronal activity induces cleavage of ECM, creating conditions for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical ECM proteoglycan, and the importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings reveal that chemical long-term potentiation (cLTP) triggers rapid brevican cleavage in perisynaptic regions through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process requires NMDA receptor activation and involves astrocytes. Interfering with cLTP-induced brevican cleavage prevents the formation of new dendritic protrusions in CA1 but does not impact LTP induction by theta-burst stimulation of CA3-CA1 synapses. Our data reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.

Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.

The V-SVZ niche is vital for adult neurogenesis in mammals, yet its regulation in humans remains poorly understood. Current models, including brain organoids, fail to replicate the unique cytoarchitecture of this niche, particularly the multiciliated ependymal cells, which are essential for its function and organization. Here, we utilize GEMC1 and MCIDAS to program human apical radial glial cells into ependymal cells, employing human brain organoids as a model. This approach induces premature ependymal cell differentiation and reorganization of the embryonic neurogenic niche, conferring characteristics of the human adult V-SVZ niche. Our findings highlight a molecular pathway that leads to ependymal cell generation and adult human V-SVZ niche reconstruction, providing a platform to study its development and function.

Restriction factors block multiple stages of viral infection. Here we describe how Ninjurin1 (NINJ1) controls HSV-1 infection of macrophages, a key cell type that protects mice against infection. We observe that Ninj1^-/- mouse macrophages are more susceptible to HSV-1 infection than WT cells. Given the role of NINJ1 during cell death, we investigate whether its antiviral activity is linked to this function. Surprisingly, we do not observe differences in cell death at early timepoints post HSV-1 infection between genotypes. Instead, we attribute the higher infection rate of Ninj1^-/- macrophages to enhanced entry, with more viral particles entering each cell and a greater fraction of infected cells. The increased viral loads in Ninj1^-/- cells result in higher ISG and cytokine RNA expression, which we ascribe to both TLR signaling and STING-mediated recognition. Cytokine secretion, however, is severely dampened in infected Ninj1^-/- cells, pointing to greater viral replication suppressing the induction of inflammation. In conclusion, NINJ1 acts as a gatekeeper for HSV-1 entry in macrophages, impacting the inflammatory phenotype associated with HSV-1 infection.

Plant-microbiome interactions are crucial in shaping plant growth, stress resilience, and disease resistance. Among these, the seed microbiome plays a pivotal role in early plant development and ecological adaptation. However, little is known about the factors that determine the abundance and functions of the seed microbiome, as well as the role of the host genome in shaping the microbial diversity across different ecotypes. In this study, we investigated the diversity of the Arabidopsis seed microbiomes that originate from multiple geographical locations. High-throughput sequencing identified key bacterial taxa that govern Arabidopsis seed microbiota diversity. Distinct compositions of bacterial taxa were identified in Arabidopsis accessions sharing geographical location and similar soil features. Genome-wide association studies (GWAS) revealed that both the abundance of key taxa and common functional traits are associated with specific host genetic loci such as the RNA-binding protein RPB47B, mutants of which showed altered physiological properties related to soil properties and microbial diversity. Overall, our study establishes that geographical, soil and genetic host factors shape the Arabidopsis seed microbiome.

Fluorescent proteins and peptide tags are essential tools in cellular biology, but can alter the biochemical and physiological behavior of target proteins. Biomolecular condensates, which have emerged as key elements of cellular organization, are suggested to provide robustness to cells, yet they can also respond sensitively to small changes in environmental conditions including tags. Here, we investigate the effects of over twenty widely used tags on condensate formation in vitro, in cells, in various model organisms and by computational modelling. We find that tagging strongly influences condensation for some proteins, while others remain unaffected. Effects vary, with some tags enhancing and others decreasing condensation, with the outcome depending on the protein being tagged. Coarse-grained simulations suggest that the charge of the fluorescent protein tags is a critical factor modulating condensation behavior. Together, our results underscore the need to tag with caution and highlight the importance of careful experimental design and interpretation, especially in condensate studies, but also suggest that fluorescent protein tags could serve as a tool to modulate condensate properties.