Inositol 1,4,5-trisphosphate receptors (IP3Rs) are an important class of ion channels that mediate calcium (Ca2+) release from the endoplasmic reticulum and other organelles, thereby critically controlling cell function. Dysregulation of these channels, including excessive IP3R activity, has been implicated in a plethora of diseases. The current arsenal of tools to acutely inhibit IP3Rs consists of various antagonists with distinct mechanisms of action. Yet, most suffer from limited selectivity due to their impact on several other Ca2+-transport systems, cellular targets, and/or lack of membrane permeability. This shortage of highly specific IP3R antagonists limits biomedical research and hampers the development of therapeutic strategies targeting IP3R channels. This work aims to provide a comprehensive overview of IP3R-antagonizing tools that were developed and characterized over the past decades, focusing on three classes of molecules: (1) pharmacological antagonists that directly affect IP3Rs by binding to the channel, (2) biological antagonists that directly affect IP3Rs by interacting with the IP3R, and (3) antagonism of IP3R activity via regulation of the phosphoinositide signaling pathway upstream of IP3Rs.

During preimplantation development, mammalian embryos form blastocysts. Studies in mouse embryos have revealed multiple roles of the Hippo signaling pathway in this process. Among them, the process of TEA domain transcription factor 4 (TEAD4)-Yes-associated protein (YAP) control of trophectoderm (TE) and inner cell mass fate is the most extensively characterized. The major mechanism of YAP regulation is the activation of Hippo signaling by adherens junctions and inhibition by cell polarization or the apical domain. Several additional mechanisms further modulate Hippo signaling and/or YAP, including polarity regulation by Rho-associated coiled-coil-containing protein kinase (ROCK) and transcription factor AP-2γ (TFAP2C), angiomotin (AMOT) regulation by Ras homolog (RHO), asymmetric inheritance of the apical domain, mechanical regulation, and glucose metabolism. Hippo signaling also regulates other processes during embryogenesis, including zygotic gene activation by maternal YAP, cell state transition at the 8-cell stage, and maturation and quality control of the epiblast via cell competition. The TE fate regulatory role of the Hippo pathway is evolutionarily conserved among mammalian species, including human and bovine embryos, but some details differ.

In various eukaryotic organisms, amoeboid cells undergoing spontaneous migration generate membrane protrusions and establish front-rear polarity in an autonomous manner through signal transduction networks that couple excitable Ras dynamics to downstream bistable modules. Recent genetic and live-cell imaging studies in Dictyostelium cells have identified Ras GTPase and the newly characterized guanine nucleotide exchange factor RasGEFX as core drivers of this excitability, amplifying stochastic basal Ras activity into discrete signaling patches and propagating waves. These excitatory events initiate pseudopod formation even in the absence of external guidance cues and engage the bistable PIP3-PTEN switch to stabilize cell polarity. The same Ras excitable network also drives constitutive macropinocytosis, revealing a shared mechanism for membrane protrusion and fluid uptake. This hierarchical excitable-bistable architecture, coupled with motile machinery, converts intrinsic molecular noise into structured, non-Brownian exploratory behavior, representing an adaptive strategy that enables cells to exploit stochasticity for navigation in complex natural environments.

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.

Neural crest cells are among the most migratory cells in the vertebrate embryo. They initially arise within the forming neural tube, the precursor to the brain and spinal cord, but then migrate away by undergoing an epithelial-to-mesenchymal transition (EMT). Different neural crest populations exist along the body axis that differ in their flavor of EMT, migratory pathways, and cell types into which they differentiate. In the head region, neural crest cells interact with ectodermal placodal cells, another migratory cell type unique to vertebrates, that form sensory structures of the head. Here, we focus on select neural crest and placodal populations, highlighting how their region-specific migrations may be linked to cell fate choices and discuss how neural crest-placode interactions influence each other's behavior and derivative formation.

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.

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.

The collection of articles on the theme Evolution and Development of Neural Circuits explores how brains are built, diversified, and adapted in a variety of species, integrating perspectives from evolutionary biology, developmental neuroscience, and systems neurobiology. Recent advances in molecular genetics, neuroanatomy, physiology, imaging, and computational modeling have enabled unprecedented insights into the mechanisms that shape neural circuits. This collection brings together contributions from leading investigators who examine the architecture and function of neural circuits from multiple angles. Key themes include the evolutionary divergence and convergence of circuit motifs, the conserved molecular and developmental building blocks that underlie connectivity, and the selective pressures that sculpt neural systems to support behavior and cognition. Articles cover topics ranging from retinal mapping and interneuron diversity to thalamocortical connectivity, prefrontal circuit maturation, and the computational modeling of both normal and abnormal circuit development. Collectively, these essays reveal how molecular signaling, cellular variability, and theoretical principles converge to shape the formation and function of circuits across vertebrate and invertebrate brains.

Basic research that established how the cell cycle is regulated has been critical to our understanding of carcinogenesis and paved the way for new treatments like palbociclib and ribocilib. Mitosis was first observed almost 150 years ago, and the phases of the cell cycle were defined midway through the twentieth century. Subsequent studies in yeast, frogs, mice, and human cells identified the molecular machinery that controls entry into the cell cycle, including cyclin-dependent kinases, their regulators, and the product of the retinoblastoma (RB) gene. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the work that discovered these key molecules and mapped the RB pathway that controls the G1/S transition.