Cell reports最新文献

In humans, cadmium (Cd) toxicity caused by contaminated environments is associated with numerous chronic diseases. Breeding rice with low Cd accumulation is now deemed critical for sustainable agriculture development. Here, we elucidate the crucial functions of UCLACYANIN 23 (UCL23), a small copper protein, in Cd absorption, tolerance, and accumulation through modulation of reactive oxygen signals in rice. Additionally, we demonstrate that WRKY51 binds to promoters of UCL23 and miR528, a post-transcriptional regulator of UCL23, thereby contributing to Cd regulation in a dual-modulatory manner. Furthermore, we show that the natural variation of UCL23 is important for the differential accumulation of Cd in rice grains. Finally, we reveal that Indica rice harboring the major Japonica haplotype of UCL23 significantly reduces Cd uptake in roots and Cd accumulation in grains. Together, our study not only reveals a regulatory cascade in Cd regulation but also provides valuable resources for breeding low-Cd rice cultivars.

During the second cell fate in mouse embryos, the inner cell mass (ICM) segregates into the spatially distinct epiblast (EPI) and primitive endoderm (PrE) layers. The mechanism driving this pattern formation, however, remains unresolved. Here, we report that, concomitant with the segregation process of EPI/PrE precursors starting from mid-blastocyst, the blastocyst cavity begins to oscillate cyclically with rapid contraction yet slow expansion, triggering a phase transition in the ICM to a fluid-like state. This asymmetric oscillation of the blastocyst cavity facilitates EPI/PrE segregation by enhancing cell-cell contact fluctuations within the ICM and initiating convergent cell flows, which induce movement of these two cell types in opposite directions, wherein PrE precursors move toward the ICM-lumen interface, whereas EPI precursors move toward the trophectoderm. Last, we found that both PDGFRα expression and YAP nuclear accumulation in PrE precursors increase in response to blastocyst cavity oscillation. This study reveals the foundational role of physical oscillation in driving embryonic pattern formation during early mammalian embryonic development.

The brain environment is uniquely specialized to protect its neuronal tissue from excessive inflammation by tightly regulating adaptive immunity. However, in the context of brain cancer progression, this regulation can lead to a conflict between T cell activation and suppression. Here, we show that, while CD8⁺ T cells can infiltrate breast cancer-brain metastases, their anti-tumor cytotoxicity is locally suppressed in the brain. Conversely, CD8⁺ T cells exhibited tumoricidal activity in extracranial mammary lesions originating from the same cancer cells. Consequently, combined high-dose irradiation and anti-programmed cell death protein 1 (PD1) therapy was effective in extracranial tumors but not intracranial lesions. Transcriptional analyses and functional studies identified neutrophils and Trem2-expressing macrophages as key sources for local T cell suppression within the brain, providing rational targets for future therapeutic strategies.

Sex steroid hormones such as progesterone play a pivotal role in reproductive functions and maintaining pregnancy; however, the impact of progesterone on the interaction between mother and embryo is unclear. Here, we demonstrate that the relationship between maternal progesterone and membrane progesterone receptor epsilon (mPRε) in adipose tissue regulates embryonic nutritional environment and growth after birth in mice. The activation of adipose mPRε by increased progesterone during pregnancy enhances maternal insulin resistance via prostaglandin production, efficiently providing glucose to embryos. Correspondingly, the offspring of mPRε-deficient mothers exhibited metabolic dysfunction, whereas mPRε-deficient mothers with high-fat diet-induced obesity exhibited improved insulin sensitivity. These findings establish the importance of progesterone as a nutritional regulator between mother and embryo. Additionally, mPRε may represent a modulator for treating pregnant glycemic control disorders such as gestational diabetes mellitus, as well as metabolic syndrome in offspring.

Glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for synapse formation between hypothalamic glucoregulatory centers. Although microglia prune synapses throughout the brain, their role in refining hypothalamic glucoregulatory circuits remains unclear. Here, we show that the phagocytic activity of microglia in the mediobasal hypothalamus (MBH) is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In addition to actively engulfing synapses, microglia are critical for refining perineuronal nets (PNNs) within the neonatal MBH. Remarkably, transiently depleting microglia before weaning (postnatal day [P]6-16) but not afterward (P21-31) induces glucose intolerance in adulthood due to impaired insulin responsiveness, which we link to PNN overabundance and reduced synaptic connectivity between hypothalamic glucoregulatory neurons and the pancreatic β cell compartment. Thus, microglia facilitate early-life synaptic plasticity in the MBH, including PNN refinement, to program hypothalamic circuits regulating adult glucose homeostasis.

Nearly 850 million people suffer from kidney disease worldwide. Genome-wide association studies identify genetic variations at more than 800 loci associated with kidney dysfunction; however, the target genes, cell types, and mechanisms remain poorly understood. Here, we show that nucleotide variants on chromosome 15 are not only associated with kidney dysfunction but also regulate the expression of Wasp homolog associated with actin, membranes, and microtubules (WHAMM). WHAMM expression is higher in mice and patients with chronic and acute kidney disease. Mice with genetic deletion of Whamm appear healthy at baseline but develop less injury following cisplatin, folic acid, and unilateral ureteral obstruction. In vitro cell studies indicate that WHAMM controls cell death by regulating actin-mediated cytochrome c release from mitochondria and the formation of ASC speck. Pharmacological inhibition of actin dynamics mitigates kidney disease in experimental models. In summary, our study identifies a key role of WHAMM in the development of kidney disease.

Although only a fraction of tumor cells contribute to metastatic disease, no prognostic biomarkers currently exist to identify these cells. We show that a physical marker-adhesion strength-predicts metastatic potential in a mouse breast cancer model and that it may stratify human disease. Cells disseminating from murine mammary tumors are weakly adherent, and, when pre-sorted by adhesion, primary tumors created from strongly adherent cells exhibit fewer lung metastases than weakly adherent cells do. We demonstrate that admixed cancer lines can be separated by label-free adhesive signatures. When applied to murine metastatic tumors, adhesion retrospectively predicts metastatic disease with 100% specificity, 85% sensitivity, and area under the curve (AUC) of 0.94. Cells from human reduction mammoplasties have a higher adhesion strength versus resected human tumors, which may also be stratified between invasive and more indolent cancers. Thus, highly metastatic cells may have a distinct physical phenotype that may be a predictive marker of clinical outcomes.

Learning the causal structures of social environments involves predicting significant events (e.g., rewards) and detecting prediction errors for each agent. Whether the brain can simultaneously compute reward prediction errors for self (S-RPE) and others (O-RPE), and which neurons are responsible, is unclear. Here, we condition two monkeys with identical visual stimuli predicting different reward outcomes and find that dorsomedial prefrontal neurons represent both S-RPE and O-RPE simultaneously. Neuronal signatures of RPE are agent and sign specific, forming distinct populations for positive and negative S-RPE and O-RPE. A linear decoder trained on neurons encoding O-RPE, but not S-RPE, successfully discriminates RPE. Further investigation identifies coexisting actual reward and prediction confirmation signals for others. These results highlight the presence of neuronal mechanisms in the primate brain that update the value of environmental stimuli simultaneously for oneself and others, enabling primates to comprehend the causal structure of the world from the perspective of others.

Gamma-frequency oscillations are a hallmark of active information processing and are generated by interactions between excitatory and inhibitory neurons. To examine the contribution of distinct inhibitory interneurons to visually induced gamma oscillations, we recorded from optogenetically identified PV+ (parvalbumin) and Sst+ (somatostatin) interneurons in mouse primary visual cortex (V1). PV and Sst inhibitory interneurons exhibited distinct correlations to gamma oscillations. PV cells were strongly phase locked, while Sst cells were weakly phase locked, except for narrow-waveform Sst cells. PV cells fired at a substantially earlier phase in the gamma cycle (≈6 ms) than Sst cells. PV cells fired shortly after the onset of tightly synchronized burst events in excitatory cells, while Sst interneurons fired after subsequent burst spikes or single spikes. These findings indicate a main role of PV interneurons in synchronizing network activity and suggest that PV and Sst interneurons control the excitability of somatic and dendritic neural compartments with precise time delays coordinated by gamma oscillations.

Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.