Cell Biology

eLife assessment

This manuscript describes a useful tool for quantitative assessment of sarcomere structures in healthy and perturbed cardiomyocytes grown in vitro. The work is solid, and the methods, data and analyses broadly support the claims with only minor weaknesses. The tool will be relevant to biologists working on and interested in obtaining quantitative information on sarcomere structure, function and development.

eLife assessment

Protein and lipid homeostasis are important for maintaining cellular functions but their crosstalk remains largely unknown. This important manuscript deals with this interesting topic and applies the powerful unbiased tools of somatic cell genetics to discover evidence suggesting a link between sphingolipids/cholesterol ester metabolism and lysosomal protein aggregation. However, in our view the experimental evidence in support of the paper's stated conclusions remains incomplete and measures that (i) go beyond reliance on the ProteoStat stain as the sole metric for aggregation and proteostatic challenge, (ii) biochemically back up the results and provide plausible mechanistic insights into the connection of lysosomal lipid handling and protein aggregation are needed.

eLife assessment

The authors present a useful analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes. The evidence is currently still incomplete as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study confirms and extends previous findings and will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment

This study presents the valuable finding that a cleaved form of METTL3 (termed METTL3a) has an essential role in regulating the assembly of the METTL3-METTL14-WTAP complex. The evidence supporting the claims of the authors is solid, and the work will be of interest to medical biologists working on breast cancer.

eLife assessment

This important study provides exciting first-time evidence linking palmitate-induced insulin resistance to ceramide accumulation within the mitochondrial compartment and subsequent depletion of CoQ, an essential component of mitochondrial respiration. Whereas the results and interpretations are generally solid, the mechanistic aspect of the work and conclusions put forth rely heavily on in vitro studies performed in cultured L6 myocytes, which are highly glycolytic and generally not viewed as a good model for studying muscle metabolism and insulin action. Nonetheless, the findings offer intriguing new insights into mechanisms that connect ceramides to both insulin resistance and mitochondrial dysfunction, and are likely to open new avenues of preclinical/clinical research with broad therapeutic implications.

eLife assessment

This work explores how centrosomes, which function as the primary microtubule organizing center in animal cells, regulate cell division by examining the process in cells in which centrosome formation has been inhibited. The carefully conducted experiments provide convincing support for the important observation that elongated, but successful, mitosis observed in cells lacking centrosomes is due to delays in cell cycle progression, though the reviewers highlight some caveats that merit further discussion.

eLife assessment

In this important study, the authors provide compelling evidence that the interplay between alternative polyadenylation (APA) of mRNA encoding Aurora Kinase A (AURKA) and hsa-let-7a miRNA governs AURKA protein levels. The authors show that short 3'UTR isoform of mRNA encoding AURKA is efficiently translated throughout the cell cycle, while the long 3'UTR isoform is suppressed by hsa-let-7a miRNA in a cell cycle-dependent manner. These findings delineate post-transcriptional mechanisms regulating AURKA expression that may be implicated in increase in AURKA protein that is frequently observed across a variety of cancers.

eLife assessment

Seelbinder et al. describe a new method for perturbing chromatin in living cells by local heating. Employing this approach, the authors uncover interesting behaviors that underscore the variability in the mechanical response of subnuclear domains and structures. The study is timely, and if some conceptual and technical aspects are improved, it should be of broad interest to both the cell biophysics and cell biology communities, in particular since the method can also be applied to study mechanical relationships of subcellular compartments in other cellular and multicellular systems.

eLife assessment

The authors show that tunneling nanotubes or TNTs are used by cells to transfer full-length mRNAs. The data show that as much as 1% of the endogenous mRNA are passed between cells by this procedure. The transferred mRNA affect the transcriptome of the acceptor cells thus highlighting the significance of this nanotube mediated trafficking of mRNA between cells. We appreciate the difficulty of this exercise. The strength of the presented evidence could be questioned based on technical limitations.

eLife assessment

This study reports the important finding that there appears to be a timer that monitors the repair of DNA after damage and regulates whether cells are subsequently able to enter mitosis. The authors identify proteins important for this decision and propose a mechanism supported by solid but not conclusive data. This study will be of interest to researchers in the fields of DNA damage repair and cell cycle control.

eLife assessment

This study combines experiments in developing embryos and embryo extracts to investigate a fundamental relationship in biology - how the size of mitotic chromosomes scales with changes in cell size during development. By combining the unique tools available in the Xenopus system with modern genomic approaches, the authors convincingly demonstrate that mitotic chromosome scaling is mediated by differential loading of maternal chromatin remodeling factors during interphase. Although it remains unclear exactly how these factors impact chromosome size, the findings reported here will be of broad interest to the cell biology community and are likely to spawn new avenues of experimental inquiry aimed at understanding intracellular scaling relationships.

eLife assessment

This study describes important results and convincing evidence linking myofibroblast senescence in the aged heart with a pro-arrhythmogenic phenotype. This is in turn related to higher mortality after myocardial infarction in the aged rabbit heart. These constitute important empiric as opposed to detailed findings. They nevertheless will be of interest to clinician scientists studying cardiac function and disease.

eLife assessment

The study provides evidence that the hormone PTH increases bone mass by, at least in part, regulating the factor Zfp467. In turn, Zfp67 controls expression of the receptor for PTH, thus creating a feedback loop that overall augments bone mass. The findings are novel and of potential great interest. Overall, the study is of interest to a broad audience and significant as it unveils a novel feedback loop involving PTH, a critical endocrine regulator of calcium, phosphate, and bone mass.

eLife assessment

In vertebrates, ciliary motility is powered by axonemal dyneins, known as OADs, tethered to doublet microtubules by a pentameric docking complex including the Armc4 and Calaxin subunits. This valuable study combines zebrafish genetics with cryo-electron tomography to convincingly show that Armc4 plays a critical role in the docking of OAD and that Calaxin stabilizes the molecular interaction. The work will be of interest to those studying the structure and function of the axoneme, and motile cilia in general.

eLife Assessment

The study has advanced our mechanistic understanding of lung regeneration. While the importance of regeneration of alveolar capillaries for long response to injury has been long recognized, the regulation of this process has not been well understood. Your study provides novel, comprehensive, and compelling evidence that the expression of the transcription factor Atf3 in alveolar capillary endothelial cells plays a critical role in the regeneration of alveolar capillaries following lung injury.

eLife assessment

This study concerns an important area, that of monoallelic expression, but the study does not provide sufficient information about the candidate regulatory RNA to provide a significant advance over previous work, which should also be discussed in more detail.

eLife assessment

This manuscript will be of interest to scientists in the field of tissue injury and repair. It provides novel molecular mechanisms of a transcription factor, Prrx1, in fibroblast activation following lung injury. Overall, the work suggests that PRRX1 plays a functional role downstream of TGFb1 to elicit some aspects of the fibrotic response and that PRRX1 could represent an important therapeutic target to treat fibrosis. The strengths of this work are the multiple approaches applying human and mouse lung tissue used by the authors to test the role of PRRX1 in lung fibrosis, however, in its current form, major limitations need to be addressed.

eLife assessment

This is a useful study for scientists interested in cell polarity, epithelial morphogenesis, cancer, and primary cilia. The authors investigate the role of CRB3 in regulating these processes by using a combination of a mammary epithelial cell-specific conditional Crb3 knockout mouse model, and cellular, molecular and biochemical approaches. The results, which are solid, supporting and extending previous findings, suggest that CRB3 affects ciliogenesis by a mechanism involving Rab11 and gamma-TuRC.

eLife assessment

This important study reports investigation of the dynamics of PKA at the single-cell level in in vitro and in epithelia in vivo. Using different fluorescent biosensors and optogenetic actuators, the authors dissect the signaling pathway responsible for PKA waves, finding that PKA activation is a consequence of PGE2 release, which in turn is triggered by calcium pulses, requiring high ERK activity. The evidence supporting the claims is solid. At this stage the work is still partly descriptive in nature, and additional measurements would increase the strength of mechanistic insights and physiological relevance.

eLife assessment

This valuable study addresses the anticipated but poorly understood interconnections between ER proteostasis and lipid metabolism. The authors discovered key metabolic enzymes required for integration of ER stress and lipid synthesis and followed up with several direct experiments that provide solid evidence for a broad conservation of the described interactions.