Cold Spring Harbor perspectives in biology最新文献

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are tetrameric calcium (Ca²⁺) release channels localized in the endoplasmic reticulum (ER), where they regulate cellular function by mediating local and global Ca²⁺ fluxes toward the cytosol, cell membrane, and organelles including mitochondria. Disruptions in these Ca²⁺ signals, whether excessive or diminished, due to alterations in IP₃R function have been implicated in a wide range of diseases and pathophysiological conditions. Consequently, the Ca²⁺-flux properties, protein abundance, and localization of IP₃Rs must be tightly regulated. Various mechanisms, including interactions with accessory proteins, ensure proper IP₃R function across diverse physiological contexts. In this review, we highlight the role of posttranslational modifications (PTMs) in modulating IP₃R activity, including phosphorylation/dephosphorylation, redox modifications, glycosylation, palmitoylation, ubiquitination, proteolysis, and transglutaminase-mediated cross-linking. We discuss not only the functional consequences of these PTMs but also provide structural insights when specific modified IP₃R residues have been identified. Furthermore, whenever possible, we emphasize IP₃R isoform-specific effects of PTMs, offering a nuanced perspective on their regulatory significance.

Telomeres represent a molecular nexus where genome stability, aging, disease susceptibility, and regenerative potential converge. Advances in understanding how telomeres are replicated, protected, and repaired now inform fundamental questions about human lifespan, tissue renewal, the molecular origins of age-related decline, and cancer evolution. This volume presents an integrated collection of perspectives spanning telomere architecture, replication dynamics, telomere-driven genome instability, and telomere maintenance by telomerase and Alternative Lengthening of Telomeres (ALT), while also charting new therapeutic directions grounded in telomere biology. Drawing on molecular, structural, organismal, and clinical research, this collection showcases a field in rapid motion, reshaping our view of regeneration, aging, and disease.

Collective migration is a key mechanism during embryonic development, particularly during gastrulation when the basic three-dimensional body plan is established. During this critical phase, mesoderm and endoderm tissues internalize from the surface to form the embryo's inner structures through species-specific processes. This internalization involves extensive collective migration of large cohorts of mesenchymal cells along characteristic routes inside the embryo. Despite decades of research, the mechanisms that control and guide the movement of these cells to their destinations remain largely unresolved. Understanding these complex interactions remains a central challenge in developmental biology. This review examines complementary insights obtained through the study of multiple vertebrate model systems-frogs, fish, chick, mouse-as well as embryonic stem cell-derived gastruloids. The evidence points to key roles for chemotactic movement and guidance mechanisms operating in concert with dynamic changes in cell-cell and cell-substrate adhesion. Recent studies have increasingly revealed critical roles for cell- and tissue-generated mechanical stresses and mechanosensing in executing and coordinating motion. Furthermore, dynamic feedback between signaling and motion generates emergent properties that enable large-scale coordination of collective migration.

The PIEZO1 and PIEZO2 membrane proteins form uniquely structured calcium permeable nonselective cation channels dedicated to mechanical force sensing in eukaryotic cells. In this review of the scientific literature, we address PIEZOs in the heart. PIEZOs enable the formation of the aortic valve, cardiac vasculature, and pericardial drainage. In the established heart, they enable baroreceptor pressure sensing and reflex regulation of the heart rate and influence the heart's size and stiffness through roles in cardiac myocytes and cardiac fibroblasts. Therefore, mechanical force sensing by PIEZOs participates in normal cardiac development and function. There is also interest in PIEZOs in pathophysiology, when the structure and mechanical properties of the heart often change. Studies in rats and mice suggest that experimentally induced cardiac stress and injury cause PIEZO upregulation that is adverse. Similar changes may occur in human heart disease, creating potential for therapeutic benefit through PIEZO modulation. This is a productive, accelerating, and exciting new research topic with importance for our understanding of the heart and its diseases.

Cell migration phenomenon has inspired and benefited from computational modeling for decades. Here, we review recent applications of traditional bottom-up modeling to three aspects of cell migration: the role of membrane tension (MT) in organizing directional cell motility, the role of the electric field (EF) as the directional cue for migration, and the mechanics of three-dimensional migration. We then discuss nascent applications of machine learning (ML) to cell migration and galvanotaxis. We focus on the migratory mechanisms of the single cell and highlight the feedback between theory and experiment.

Over the years, the fission yeast has become a reference model for telomere biology studies as this organism shares with mammals a highly conserved telomere composition. Here, we highlight the latest discoveries in telomere replication in fission yeast and show how this research brings new insights into the understanding of the replication and maintenance of mammalian telomeres.

Skeletal muscle owes its plasticity and ability to regenerate following severe injury to the resident somatic stem cells, termed satellite cells, of which a subset represent multipotent muscle stem cells (MuSCs). Adult MuSCs originate from mesoderm-derived somitic cells during embryonic development and are necessary for the maintenance and regeneration of skeletal muscle throughout life. In adult muscle, MuSCs reside under the basal lamina where extrinsic cues modulate their quiescence in resting conditions and activation in response to injury. The process of MuSC activation is highly regulated by the niche microenvironment, and perturbations that impact the MuSC-niche interaction can have deleterious effects on muscle regeneration. Here, we discuss the embryonic origin of skeletal muscle and MuSCs; the regulation of MuSC activation, self-renewal, and commitment; and myopathies that impact MuSC function.

Beyond their well-known roles in chromosome end protection, telomeres play critical roles in ensuring the fidelity of meiosis, the specialized cell division underlying sexual reproduction. Central to this process is the conserved telomere bouquet, a polarized nuclear arrangement in which telomeres cluster beneath the centrosome. The telomere bouquet orchestrates movements of meiotic chromosomes that facilitate pairing and recombination between homologous chromosomes, the defining events of meiosis. Here, we review both this canonical function and newly discovered meiotic telomere functions. We focus on three species-fission yeast, budding yeast, and mouse-that highlight both general principles and novel insights likely to be broadly applicable across eukaryotes. We propose that these diverse telomere functions provided early eukaryotes with a powerful adaptive advantage, contributing to the evolutionary success of linear chromosomes.

How biological systems obtain their shape and structure is a fundamental question with many practical implications. Like much of biology, over the last several decades, tissue and organ morphogenesis has focused on uncovering regulatory mechanisms at the cellular and subcellular scales. Such studies have either implicitly or explicitly reified the view that the creation of form is instructed or controlled by a combination of genetic and molecular processes. However, pioneering early twentieth century biological theorists such as Conrad Waddington cautioned against the total subsummation of biology by, for instance, biochemistry and molecular biology. Through the coining of terms such as "epigenotype," it was argued that processes at every scale between genotype and phenotype were necessary to organize morphogenesis. Thus, organizing processes exist that are not reducible merely to the sum of inputs from "genes" and "environment." Here, we argue that uncovering generative epigenetic processes beyond the cell yet within the organism requires a holistically oriented use of physical concepts involving mechanics and material phases. To uncover and clearly articulate such "supracellular" processes, we discuss how relations between mesenchymal cells and extracellular matrix (ECM) serve as a powerful model system. Based on the study of mesenchymal-ECM systems, we suggest that it may not be possible to understand the ultimate functional role of gene products such as signaling molecules without an appreciation of supracellular processes in their own right.

Cell migration is a fundamental biological process central to a number of physiological and pathophysiological events. Traditional genetic and pharmacological approaches have identified crucial molecular regulators of migration, yet they often lack the spatial and temporal resolution required to interrogate the highly dynamic signaling events that govern cell locomotion. Chemogenetic and optogenetic platforms-genetically encoded inducible systems activated by chemical or light stimuli, respectively-have emerged as powerful tools for achieving precise, on-demand control over protein function in living cells. These systems enable researchers to dissect molecular signaling pathways in real time and with subcellular precision, even as cells are actively migrating. Together with advances in de novo protein design, biosensors, and live-cell imaging, inducible molecular tools are transforming our ability to manipulate and elucidate the intricate mechanisms underlying cell motility. Looking forward, the application of these technologies in animal models will be crucial for gaining deeper physiological and pathophysiological insights.