EMBO Reports最新文献

Even before the advent of multicellular life, unicellular creatures would communicate with their neighbours to coordinate their behaviours. Multicellular organisms have the particular challenge of orchestrating the differentiation of stem and progenitor cells to generate and maintain coherent functional tissues. However, stem and progenitor cells face a problem: their differentiation response can be buffeted by oscillations or stochastic fluctuations in intrinsic regulators. This generates cell-to-cell variability, which can be further compounded when extrinsic cues don't provide clear unambiguous instructions. So, left to their own devices, cells may differentiate at different rates or different directions even in response to the same cues. Fortunately, cells in multicellular organisms are not left to their own devices: they continually sense and respond to the behaviours of their neighbours. Here I discuss when, where, and how stem and progenitor cells communicate to synchronise their response to differentiation cues. I highlight technical challenges in identifying such synchronisation mechanisms, and survey emerging technologies that may help overcome these challenges.

Overcoming lysogenization defect (OLD) proteins are diverse ATPase-nucleases functioning in antiphage defense in bacteria. However, the role of these proteins in archaea is currently unknown. We describe a new class of archaeal OLD family ATPases and show that they are apparently not involved in antiviral defense but play an essential role in cell cycle progression. The gene for an OLD family enzyme in Saccharolobus islandicus REY15A, named here Cran1 (Cell cycle-related ATPase and nickase 1), cannot be deleted and exhibits cyclic expression patterns at transcriptional and translational levels, with peak expression during the transition from M-G1 to S phase. Cran1 overexpression causes significant growth retardation, cell size enlargement, and increased cellular DNA content. Cran1 displays potent nickase and ATPase activities in vitro, with the nickase activity dependent on the presence of the ATPase domain. Notably, Cran1 copurifies with chromatin-associated proteins, such as Cren7 and a histone deacetylase homolog, suggesting its involvement in chromatin-related activities. Collectively, our results suggest that Cran1 plays an important role in cell cycle progression, revealing a novel function of OLD family proteins.

Adipocytes play essential roles in lipid metabolism and energy homeostasis, with regional differences affecting their functions and disease susceptibility. However, the mechanisms underlying this regional heterogeneity remain unclear. Here we demonstrate that the Bithorax Complex (BX-C) genes, specifically abdominal A (abd-A) and Abdominal B (Abd-B), define regional differences in Drosophila larval adipocytes. Abdominal adipocytes, expressing abd-A and Abd-B exhibit unique characteristics compared to thoracic adipocytes, with active Wnt/Wingless signaling further amplifying these regional differences. Depleting abd-A and Abd-B in adipocytes delays larval-pupal transition, causes pupal lethality, and attenuates the expression of Wnt/Wg target genes, thereby dampening Wnt signaling-induced lipid mobilization. Additionally, Wnt signaling enhances the transcription of abd-A and Abd-B, establishing a feedforward loop that reinforces the interplay between Wnt signaling and BX-C genes. These findings reveal how the cell-autonomous expression of BX-C genes defines adipocyte heterogeneity, a process further modulated by Wnt signaling in Drosophila larvae.

The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

The choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterised. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.

Eukaryotic cells are highly compartmentalized, enabling sophisticated division of labour. For example, genetic information is stored in the nucleus while energy is produced in mitochondria. Despite this clear specialisation, compartments depend on intensive communication, including the exchange of metabolites and macromolecules. This is achieved through intracellular trafficking with membranous carriers such as endosomes, which constitute versatile transport vehicles. Key cargos include mRNAs and ribosomes that hitchhike on endosomes, linking RNA and membrane biology. In this review, we summarize recent advances showing how mRNAs are mechanistically attached to membranes of endosomes and lysosomal vesicles and how cargos are identified for transport. The encoded proteins illuminate the biological processes that rely on such spatiotemporal control. This is particularly true for the regulation of subcellular mitochondrial homeostasis, disclosing intensive multi-organelle networking. As a general concept, the underlying protein/protein and protein/RNA interactions exhibit significant redundancy yet are organized in a strict hierarchy with distinct core and accessory functions. This ensures both the robustness and specificity of mRNA hitchhiking.

Endosymbiosis between dinoflagellate algae and cnidaria is fundamental for coral reef health. Appropriate symbiont selection is required for sufficient host nutrient acquisition and could be tailored to increase cnidarian stress tolerance. Previous research suggested glycan-lectin interactions facilitate symbiont uptake; however, blockage of such interactions does not fully inhibit symbiosis establishment, suggesting other receptors are at play. Here, we use a combination of cnidarian model systems and human cell lines to determine if phagocytic integrins facilitate symbiont recognition and uptake. Integrins are highly expressed in the gastrodermal tissue of the host, where symbiosis takes place, and symbiont uptake alters the expression of integrins and downstream signaling molecules. Blockage of integrin binding sites with competitor peptides reduces symbiont uptake, while uptake of non-symbiotic algae, or uptake in a non-symbiotic cnidarian, is unaffected. Finally, overexpression of phagocytic integrins in human cells increases symbiont uptake, and mutation of the active binding site abolishes uptake. Our findings reveal integrins as important receptors for symbiosis establishment and shed light on the evolutionary functions of integrins during phagocytosis.