The ability to discriminate self from nonself is found throughout the tree of life and underlies a diverse range of processes, including immunity, mate choice, and cooperative social interactions. Self-/nonself-recognition also operates during development, for example, coordinating the formation of complex neural circuits. Despite this ubiquity, proteins that mediate self-/nonself-recognition are lineage-specific. Novel genetic interactions have arisen repeatedly and in a punctuated manner, in some cases even evolving de novo within the same lineages. This review examines the fundamental principles of self-/nonself-recognition across diverse taxa, focusing on the cellular and molecular mechanisms underlying discrimination, the generation and maintenance of novel recognition specificities, and how these systems have been modified over time. Together, these modifications provide a mechanistic foundation to address a central problem in evolutionary biology: the origins of vertebrate adaptive immunity, a system capable of unparalleled self-/nonself-discrimination.
RNAs are versatile polynucleotides that perform essential functions in coding, regulation, catalysis, and structural organization across all forms of life. While most RNAs function endogenously within an organism, certain RNAs, including small RNAs, messenger RNAs, long noncoding RNAs, and other RNA species, can cross organismal boundaries and regulate cellular processes in recipient organisms, a phenomenon termed "cross-kingdom" or "cross-species" RNA communication. These transferred RNAs play a pivotal role in regulating host-microbe interactions. Extracellular vesicles (EVs) are lipid bilayer-enclosed structures that serve as vehicles for transporting RNAs and other cargoes from donor to recipient cells or organisms to regulate diverse cellular processes. This review summarizes recent advances in our understanding of EVs and their functions in shuttling regulatory molecules, especially RNAs, between hosts and microbes, between hosts and parasites or pests, and even between microbes. Elucidating these mechanisms will enable the development of innovative crop protection strategies.
The cytoplasm of vertebrate cells is compartmentalized into the cytosol and several messenger RNA (mRNA)-scaffolded condensates, present at steady-state conditions and in the absence of stress. They include TIS granules and the FXR1 network and act as translation, folding, and signaling environments. Therefore, in addition to serving as templates for protein synthesis, mRNAs play essential roles in cytoplasmic organization. However, not all mRNAs function as condensate scaffolds. Whereas mRNAs with short and structured 3' untranslated regions (UTRs) usually diffuse freely and localize to the cytosol, scaffold mRNAs are characterized by long and multivalent 3' UTRs. Scaffold mRNAs are responsible for the characteristic irregular, network-like morphology of mesh-like condensates and play active, functional roles during protein biosynthesis. For example, mesh-like condensates act as folding environments for proteins with long intrinsically disordered regions, where multivalent 3' UTRs act as cotranslational chaperones to prevent protein misfolding. The scaffold function of mRNAs is also important for post-translational processes, where the mRNA-mediated proximity of signaling factors promotes cellular signaling reactions. In this review, the discovery of cytoplasmic mRNA-scaffolded mesh-like compartments and their currently known assembly principles and biological roles are discussed.
Seventy years of developmental studies have identified the cellular framework and key developmental mechanisms underpinning mammalian kidney development. This understanding has centered on rodent research, where developmental genetics in the mouse has played a particularly important role. Over the last decade, the application of developmental insight to human pluripotent stem cells, generating human cell and organoid models, has spotlighted therapeutic opportunity. This review considers human kidney development and how developmental insight is being applied toward the generation of functional human kidney cell types in pluripotent stem cell-derived kidney models and provides a perspective on advancing models for clinical impact.
Neurodevelopment is the transformation of genetic information into diverse neuronal phenotypes. Developmental signals initiate patterns of gene transcription and translation that drive progenitors toward a great variety of neurons and nervous systems. The potential from messenger RNA transcription is translated by the ribosome into protein, transforming genetic information into action throughout the cell. This review traces the molecular logic of neurodevelopment to the translation of the proteome and its phenotypes. It highlights emerging research in the neocortex, an evolutionarily recent brain region of complex cognition, where the ribosome is a sensor of developmental signals and translation is a regulator of neuronal fate commitment. Neuronal fates primed in the transcriptome of neural progenitors may be selectively translated, adding layers of spatial and temporal information to the execution of neuronal differentiation. This review aims to advance prior transcription-focused concepts toward their ultimate translation-driven outcomes in the molecular model of neurodevelopment and evolution.
Fungi are widespread on our planet and essential for life as we know it, but how did they come about? Their last common ancestor lived hundreds of millions of years ago, but its characteristics, and the contours of early fungal evolution, remain mysterious. This review synthesizes information from fungal and eukaryotic microbial diversity, geology, fossils, and evolutionary genomics to infer the early evolution of fungi, identify challenges and major gaps in our knowledge, dispel misconceptions, and propose general evolutionary principles exemplified by the fungal lineage. Even though fungi likely emerged earlier than animals or land plants, their origins and early evolution are the least studied. Reconstruction of the evolutionary and ecological portrait of the first fungi is key for deciphering life in ancient ecosystems, for understanding how fungi eventually facilitated the advent of life on land, and for inferring principles that govern fungal evolution.
The mammalian interstitium is a body-wide network of fluid-filled, prelymphatic spaces. Recent studies demonstrate that it exists at three scales in continuity both within and between organs, comprising intercellular, pericapillary, and large (or fascial) interstitial spaces, the latter including fascia, dermis, organ submucosae and capsules, vascular adventitia, and perineurium. Hyaluronic acid fills all interstitial spaces, but large interstitial spaces also contain additional structurally complex and varied extracellular matrices that support soluble factor, mechanical, and potentially electrical signaling. Here we review areas where the new anatomic concept of the interstitium has led to the re-examination of previous findings, including data on interstitial matrix composition and cell trafficking. We also identify new questions arising specifically from the finding that the interstitium is multiscale and body-wide, including questions about the characteristics and drivers of interstitial fluid flow and the role of the interstitium as a rich and active basolateral signaling compartment.
Development depends on the coordinated activity of many genes acting across time and space within each individual, yet many species can produce multiple discrete phenotypes. Such complex balanced polymorphisms are often controlled by supergenes, which are genomic regions containing tightly linked genetic elements that function together to direct alternative developmental programs. Supergene-controlled polymorphisms provide powerful models for understanding evolution and development, revealing how stable alternative fates emerge through the modulation of gene regulatory networks (GRNs). Here, we synthesize recent advances in the evolution, function, and developmental genetics of butterfly mimicry supergenes. We use these historically important systems to review how and why supergenes evolve. We then discuss how supergenes control the development of alternate wing patterns through GRN modification. Finally, we draw parallels with supergene polymorphisms in other organisms to frame general principles governing the evolution and developmental basis of balanced polymorphisms.
The scaling relationship between metabolic rate and body mass is a foundational principle in biology that links physiology, ecology, and evolution. From early empirical studies-most notably Kleiber's observation of 3/4 power law scaling-to contemporary theoretical frameworks, decades of research have sought to explain why organismal metabolic rate increases more slowly than body mass. This review examines variation in scaling exponents across the tree of life and explores how cellular features, including cell size, mitochondrial dynamics, and energy storage, shape whole-organism metabolism. We describe how dynamic metabolic rates during embryonic development reveal patterns of energy use during growth, while deviations in metabolic scaling across species and disease states indicate how biological systems balance energy constraints with adaptive flexibility. Together, these insights position cells as the critical interface linking molecular bioenergetics to organismal function, evolution, and ecology.
Cells mechanically interface with their surroundings through the actin cytoskeleton, a network of dynamic actin filaments, force-generating myosin motor proteins, and hundreds of associated binding proteins. The cytoskeleton plays a central role in the capacity of cells to sense and respond to physical forces and the mechanical properties of their environments (mechanosensing). Mechanosensing is essential for development and tissue homeostasis, and it is frequently disrupted in hereditary developmental disorders and cancers. Mechanistic studies of cytoskeletal mechanosensing have uncovered mechanically regulated binding interactions between cytoskeletal proteins, as well as force-sensitive dynamics of subcellular cytoskeletal networks that emerge at the scale of hundreds to thousands of molecules. Here, we review recent efforts to decipher the biophysical and protein structural bases of cytoskeletal mechanosensing, emphasizing emerging approaches for directly visualizing active force transduction from the angstrom to micrometer scale.
Transcription is a key process in the life of cells. In the 1990s, cell biologists observed that transcription often takes place in discrete transcription bodies in eukaryotic nuclei, which has sparked an exciting new field of research. Transcription bodies are sites of accumulated transcriptional machinery that regulate the transcription of one or multiple genes. In recent years, we have begun to understand the relationships between transcription bodies and the genome, how transcription bodies assemble, and how they impact transcriptional activity. Much, however, remains unclear: for example, how specificity in the clustering of proteins is achieved, how multiple genes come together in nuclear space, how the dynamic behavior of transcription bodies impacts their function, and in which ways transcription bodies affect transcription. In this review, we provide an overview of the current state of knowledge, as well as the open questions, and how these may be addressed using emerging technologies.
Epigenetic inheritance of repressed chromatin domains plays a central role in the stable silencing of cell type-specific genes and transposons in eukaryotes. Silent chromatin domains are associated with repressive histone modifications, and their propagation requires a read-write mechanism involving recognition of histone modifications by enzymes that also catalyze them. The recycling of parental histones during DNA replication plays a crucial role in maintaining chromatin states by providing the substrate for read-write enzymes. Here we describe recent advances in understanding how the DNA replication machinery and its associated histone chaperones mediate symmetrical parental histone transfer to newly replicated daughter DNA strands and evidence that this process is required for the epigenetic inheritance of silent chromatin domains.
Both the levels and duration of gene expression play critical roles in many biological processes. Recent studies have further revealed that the dynamics of oscillatory versus sustained gene expression also provide essential regulatory information during cell proliferation and differentiation. Oscillatory expression, governed by intracellular negative feedback loops and intercellular coupling with appropriate delays, promotes the proliferation of stem cells, whereas sustained expression typically drives cells toward quiescence or differentiation. Over time, oscillations can result in the gradual upregulation or downregulation of downstream factors or shifts in phase relationships between distinct oscillators, thereby functioning as a timer for cell state transition. Moreover, oscillation frequency encodes critical cues for cell fate choice. Thus, oscillatory dynamics add an extra dimension to the informational landscape of gene expression. Here, we discuss recent advances in our understanding of how oscillatory gene expression is regulated and how it influences the proliferation and differentiation of stem cells.
It is believed that the last common eukaryotic ancestor was a ciliated organism that used cilia for locomotion and sensation. Many extant ciliated protozoans exemplify this archetypal condition. However, in metazoans, particularly vertebrates, there appears to be a demarcation of cilia types. Thus, immotile primary cilia function in sensory neurons for the perception of environmental stimuli and in many other cells for the transduction of morphogenetic and physiological signals. By contrast, motile cilia are more restricted in their distribution, and their rhythmic beating drives fluid flow over epithelia or cellular locomotion. Here, we review the mechanisms that regulate ciliated cell specification, focusing principally on ciliogenic transcriptional networks and inductive signals that activate them in different cell lineages. We also highlight human disorders that arise from misspecification of ciliated cells and conclude with a discussion on how ciliated cell specification pathways could be utilized for the amelioration of disease phenotypes in ciliopathies.
A plant's indeterminate growth requires constant cell proliferation and stem cell maintenance to support its developmental plasticity. The root meristem is an excellent system to study the developmental control of plant cell cycles due to the organ's accessibility and the tight link between cell cycle and developmental regulation. Studies have uncovered diverse pathways that shape root tissue patterning and cell identity, but how these mechanistically connect to cell cycle components remains unclear. Recent work and new approaches are starting to bridge this gap. In this review, we synthesize recent findings on the developmental regulation of cell cycle progression across distinct cell types and developmental zones in the Arabidopsis thaliana root apical meristem, highlighting cells and regions of the root where these processes have been thoroughly studied, and others where we know little. These discoveries reveal a nuanced relationship between cell identity and cell cycle regulation that implies an active role for cell cycle modulation in the patterning and developmental plasticity that are integral to plant growth.
Local protein synthesis is a conserved mechanism that allows cells with intricate architectures to perform compartment-specific functions. By translating messenger RNAs (mRNAs) at distinct subcellular locations, cells can respond swiftly and precisely to localized stimuli. This strategy is crucial in neurons, whose long processes extend far from the cell body. Disruptions in neuronal local translation have been implicated in neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, and spinal muscular atrophy. While much of the spotlight has been on neurons, glial cells-microglia, astrocytes, oligodendrocytes, and radial glia-are increasingly recognized for their own dynamic use of local translation. These support cells exhibit asymmetric mRNA localization, suggesting that local protein synthesis plays key roles in their diverse functions. This review explores the emerging landscape of local translation in glial cells and examines how this finely tuned process contributes to both normal brain function and the development of neurological disease.
Stem cells are undifferentiated cells capable of self-renewal and differentiation into specialized cell types, forming the foundation of tissue maintenance and repair. In the blood system, this process is known as hematopoiesis. Hematopoietic stem cells (HSCs), positioned at the apex of the hematopoietic hierarchy, have the unique ability to reconstitute the hematopoietic system long-term. HSC stemness is defined by multipotency, allowing differentiation into all blood lineages, and self-renewal, maintaining the stem cell pool. A fundamental property of HSCs is quiescence, which refers to a reversible inactive cell cycle state that preserves their self-renewal potential. Dormant HSCs represent a subset of quiescent stem cells with minimal division rates and the most potent stemness. Dysregulation of dormancy and quiescence is linked to HSC dysfunction. Here, we explore mechanisms regulating HSC dormancy and quiescence under homeostatic and stress conditions. Finally, we describe how factors such as aging, inflammation, and malignancies disrupt these states.
The neural crest is a highly migratory multipotent cell population traveling large distances in the vertebrate embryo. Neural crest cells migrate collectively in subpopulations, ranging in size from streams with hundreds of cells delaminating in the cephalic region to chains of single cells that delaminate in a dripping manner in the trunk. Here, we review the guidance mechanisms involved in neural crest migration and stream formation. We first describe established concepts of neural crest chemosensing and then highlight novel insights into biomechanical guidance. Finally, we propose how chemical and mechanical cues might interact and how neural crest cells can self-generate guidance gradients, facilitating robust guidance. Through this, we describe the mechanisms enabling neural crest cells to swarm collectively over large distances in a coordinated and directional manner within the complex in vivo environment of an embryo.
Gene clusters generate proteome diversity required for cell fate and function. Given their genomic organization, wherein tandemly arranged genes with nearly identical promoter sequences neighbor shared enhancers, gene clusters present extreme cases of enhancer-promoter specificity, long-range enhancer-promoter communication, and chromatin compartmentalization. Here, we review recent advances in the regulation of protocadherin (Pcdh) and olfactory receptor (OR) gene clusters. These clusters present similar challenges in that cells must express a limited number of each type of gene stochastically. Probabilistic Pcdh and OR choice is accomplished through tunable enhancer-promoter interactions, but these interactions are regulated by distinct mechanisms. At the Pcdh locus, cohesin-mediated DNA loop extrusion dictates enhancer-promoter communication, whereas OR genes communicate with their enhancers through multichromosome assemblies involving the protein LDB1. In reviewing principles of Pcdh and OR regulation, we propose that gene clusters offer valuable paradigms for deciphering principles of gene expression regulation, with broad mechanistic and physiological implications for mammalian genome folding.
The hippocampus is critical for an array of cognitive functions arising from its complex substructure and connectivity. Important insights into hippocampal field specification emerged from classical studies that examined mice lacking particular transcription factors or signaling molecules. Recent high-throughput bioinformatics approaches have led to fresh perspectives on these findings. This review offers a semihistorical timeline of the discovery of the hippocampal organizer and examines the interplay of factors that position this structure. We compare the rich body of literature in the mouse with studies in nonmammalian vertebrates and in human-derived organoid models that reveal commonalities in the mechanisms that induce specific hippocampal fates. We also examine the regulation of neurogenesis versus gliogenesis and the migration of different cell types in the hippocampus. We discuss open questions that arise from discoveries made over the past three decades, and suggest hypotheses or approaches that will expand our understanding of the choreography of hippocampal development.
