Cold Spring Harbor perspectives in biology最新文献

It is well-known that the rediscovery of Mendelian genetics at the turn of twentieth century offered Darwin's theory a much-needed lifeline, by showing how Fleeming Jenkins' famous "blending" objection could be rebutted. However, Mendelism has another fortuitous consequence for evolutionary biology that is less widely appreciated. By bequeathing the notion of allelism to biology, Mendelism shows how two difficult conceptual issues for evolutionary theory can be resolved. The first issue concerns the notion of population. By definition, evolutionary change is change in the composition of a population, but what is the relevant definition of "population"? The second issue concerns Darwin's notion of "struggle for existence." Is this struggle an essential part of evolution by natural selection or not? In a Mendelian population, these issues can be simply resolved, since the selective competition is at root between alleles at a locus, who are necessarily playing a zero-sum game, rather than between organisms, who may or may not be doing so.

We survey a combination of classical and recent experimental and modeling developments in eukaryotic cell migration, from the subcellular processes and regulation, to single and collective cell dynamics. We showcase several examples that demonstrate simulations at several hierarchies: subcellular actin waves, corresponding migratory cell behavior, and collective behavior of several multicellular systems. We argue that the use of shared open-source software packages (such as Morpheus, in our case) to simulate multiscale models would be a boon to the community, allowing us to recreate, investigate, and build on existing work. A brief summary of currently available software is provided.

The standard genetic code, which applies almost without exception, is the key to our understanding of molecular biological processes. Although it is close to impossible to imagine that sparse code changes occur naturally given proteomic constraints, specific cases of codon usage alterations have been documented, mostly in unicellular eukaryotes. Here, we summarize what we have learned about Blastocrithidia, a little-known parasitic flagellate with all three stop codons reassigned to sense codons, which uses UAA as the only universal stop codon. We first describe its origin, life cycle, morphology, cultivation, and transformation, the combination of which predisposes it to become the first tractable eukaryote with a noncanonical genetic code. Next, we present our across-the-genome analysis revealing uneven distribution of in-frame stops and discuss the features distinguishing in-frame and genuine stop codons that allow for so-called position-specific termination. Finally, given what is known about stop codon readthrough by near-cognate transfer RNAs (tRNAs) and the fidelity of stop codon recognition by eukaryotic release factor 1 (eRF1), we propose a model illuminating how unique properties of Blastocrithidia tRNAs, combined with specific alterations of its eRF1, enable this massive deviation from the standard genetic code.

The ability of the cell to generate precise and sustained intracellular Ca²⁺ signals is governed by multiple spatial and temporal restrictions. Ca²⁺ flowing into the cell through plasma membrane channels activates multiple effectors but is limited to targets in the vicinity of the channel. To reach distant effectors, cells developed a mechanism termed "Ca²⁺ tunneling" where extracellular Ca²⁺ entering the cell through "store-operated Ca²⁺ entry" is shuttled through the lumen of the cortical endoplasmic reticulum to be released by inositol 1,4,5-trisphosphate receptors toward distal targets. Here, we review the mechanisms and functions of Ca²⁺ tunneling in light of recent findings linking the structure of the cortical endoplasmic reticulum at membrane contact sites and the organization of the tunneling machinery.

Store-operated Ca²⁺ entry (SOCE) is the primary Ca²⁺ entry mechanism in nonexcitable cells such as endothelial cells (ECs). When the endoplasmic reticulum (ER)-resident stromal-interacting molecules 1 and 2 (STIM1/2) sense the depletion of Ca²⁺ stores, they gain an extended conformation and move to interact with plasma membrane (PM) Orai channels within PM-ER junctions to trigger SOCE. Biophysically, SOCE is mediated by the Ca²⁺ release-activated Ca²⁺ (CRAC) current. SOCE was proposed to regulate many EC functions, including proliferation, migration, angiogenesis, and barrier permeability. Prior studies have provided evidence that dysregulation of endothelial SOCE underlies endothelial dysfunction in several vascular diseases. Here, we highlight the role of SOCE in regulating EC function and explore the potential of targeting Orai channels to treat vascular diseases.

Plasticity of cell migration is a hallmark of cell movement during morphogenesis, tissue repair, and cancer metastasis. Interconversions of migration modes are tissue context-dependent and range from (1) collective migration of cohesive cells, migrating as epithelial sheets and strands; (2) multicellular networks of individualized cells moving while maintaining short-lived interactions; and (3) fully individualized cells moving by mesenchymal or amoeboid migration. Modes of cell migration, which are controlled by cell-cell adhesion, cell density, and active forces, can also be represented by physics-derived parameters, including temperature, applied stress, and volume fraction in classical passive jamming phase diagrams. Cell-packing density, cell-cell adhesion strength, and intrinsic migratory capacity have been defined as the key parameters driving jamming transitions in 2D sheet models, where extracellular matrix (ECM) is typically not considered. Here, we review how plasticity of cell migration programs intersects with jamming/unjamming principles and specifically focus on the impact of ECM architectures. In three-dimensional (3D) tissues, additional spatial parameters determine cell density and cell-cell interactions, including the degree of confinement forcing cells together versus the availability of free space. Integrating mechanisms of jamming/unjamming with actin-based active movement of cells in a 3D environment, similar to the motion of active nematic droplets in a passive nematic matrix, will enable building realistic models to predict cell behaviors in physiological and pathological contexts, including cancer metastasis.

Many cell types migrate collectively, a process critical for animal development and co-opted in some medical disorders. Thus, uncovering the molecular regulation of collective cell migration is of broad interest, yet this process remains understudied as compared to individual cell motility. Both collective and individual cell movements rely on similar mechanisms to change cell shapes and adhesiveness. Although grouped cells face the added challenge of maintaining coordination and communication, they can then leverage group-level advantages, like animals in a pack. How motile cells work together to accomplish these feats is an active area of study. The border cells of the Drosophila ovary provide an ideal case for investigating collective cell migration, because they can be imaged within their native tissue and are amenable to genetic manipulation. Here, we discuss how border cell movement is controlled genetically, including recent insights into group guidance, how these cells interact with their surroundings, and how they divide up functions and coordinate behaviors.

Human telomeric heterochromatin is unusual in that it does not show the enrichment of canonical repressive histone marks H3K9me3 or H4K20me3 seen in constitutive heterochromatin. Instead, human telomeres exhibit both facultative heterochromatin and euchromatin marks, consistent with their epigenetically regulated transcription into TERRA noncoding RNA. Additionally, telomeric DNA is out of phase with the DNA helical repeat and has no nucleosome positioning signal. Yet, human telomeric DNA forms a columnar structure of tightly stacked nucleosomes, alternating with open states, and regulated by histone tails and shelterin protein binding. We discuss the proposed mechanisms regulating human telomeric chromatin and the consequences that telomeric chromatin properties have on various cellular processes, such as telomere transcription, the regulation of shelterin binding, and the activation of the alternative lengthening of telomeres mechanism. Together, we summarize current evidence on the combination of hetero- and euchromatic properties of human telomeres that may help explain their crucial protective functions and plasticity to regulate telomere maintenance pathways and damage signaling.

Recent technological advances in genome editing capabilities and live imaging capacities have greatly increased the use of the zebrafish model in skeletal muscle research, leading to critical discoveries in the cellular and molecular processes regulating skeletal muscle growth, regeneration, and disease. This is highlighted by the characterization of muscle stem cell and progenitor cell dynamics during growth, the visualization of novel cellular interactions driving regeneration, and the identification of complex disease mechanisms and potential therapies for muscle diseases. This review highlights these latest advancements and discuss the limitations and future directions of zebrafish in skeletal muscle research, focusing on muscle growth, regeneration, and disease.

Neutrophils are highly motile white blood cells that protect our body against bacterial and fungal infections. Local and global cytosolic Ca²⁺ elevations enhance the ability of neutrophils to phagocytose and kill microbes, but how Ca²⁺ signals regulate neutrophil adhesion, spreading, and trans-endothelial migration is unclear. Following the detection of chemotactic cues, selectin and integrin adhesion molecules unfold to interact with their ligands on the endothelial wall, triggering an extensive remodeling of the actin-based cytoskeleton that drives neutrophil migration and extravasation. Multiple intracellular signaling cascades are engaged by the activation of chemokine receptors, selectins, and integrins that coordinate actin-based motility and actin turnover to ensure the efficient directed migration of neutrophils to their targets. Here, we review how selectin and integrin-mediated Ca²⁺ elevations regulate neutrophil adhesion and spreading, the molecular and ultrastructural basis of localized Ca²⁺ signals in neutrophils, and the pathways decoding the Ca²⁺ signals that sustain actin-based neutrophil motility.