Retinal circuits extract visual features such as color, contrast, and motion. Direction-selective (DS) circuits provide a well-studied model for understanding how the brain builds feature-selective circuits. Recent work highlights the remarkable evolutionary conservation of DS circuit components. Across species, these circuits share common transcriptional programs that diversify DS cell types and molecular cues that help establish precise synaptic organization. Directional tuning emerges during development without visual input through gene regulatory networks, extracellular signaling, and activity-dependent mechanisms. Disruption of these processes can impair motion processing and contribute to visual and oculomotor deficits. Therefore, DS circuits provide a powerful system for dissecting the molecular programs involved in neuronal subtype diversification, neurite guidance, and synaptic development. In this review, we summarize recent advances in our understanding of DS circuits, their development, cell type composition, and tuning across species.
Stem cells must accurately balance self-renewal with the generation of specialized cells that each adopt the type of metabolism facilitating their specific function. However, recent advances demonstrate that metabolism can regulate decisions between self-renewal and differentiation, in addition to being a downstream outcome of transcriptional programs of differentiation. Here we discuss how metabolism influences mammalian stem cells, focusing on the conundrum of how cell fate determination can be accurately controlled if the endpoint product — the specialized cellular metabolism — can influence the process. We propose that most stem cells are guided by intrinsic and extrinsic metabolic cues, creating dynamic metabolic states that may differ in lineage preferences and activity but do not pose a deterministic impact on stem cell potency. Such metabolic plasticity safeguards tissue maintenance and regeneration from modest metabolic fluctuations, but disruptions beyond the limits of metabolic plasticity can impair stem cell function and fate potential.
Emerging work is shedding light on how integrin engagement can be harnessed to modulate cell behaviour by deepening our understanding of the downstream signalling cascades activated upon extracellular matrix (ECM) binding. In many culture systems, integrin-mediated adhesion works in concert with exogenously supplied growth factors or small molecules to guide differentiation. Altogether, cell-ECM interactions via integrin-mediated adhesion are a driving force in regulating stem cell fate. In this mini-review, we highlight key studies that demonstrate how the ECM influences lineage specification in both in vivo and in vitro settings, and we discuss how these insights may shape the future of organoid culture systems.
Endogenous retroviruses (ERVs) are dynamically regulated across the lifespan and can function as context-dependent components of host gene-regulatory networks. During embryonic development, selected ERV-derived elements are co-opted to support zygotic genome activation, lineage specification, and placental development. In adult tissues, ERV-derived sequences can contribute to tissue and immune homeostasis, whereas potentially disruptive ERV activity is constrained by epigenetic mechanisms. During regeneration and somatic cell reprogramming, ERV and broader transposable-element programs undergo transient, locus-specific remodeling. In aging, the weakening of epigenetic and nuclear restraint can promote aberrant ERV derepression, inflammation, and functional decline. This review summarizes the diverse roles of ERVs across these contexts and discusses the challenges of defining locus-specific functions, resolving repetitive sequences, and developing safe ERV-targeted interventions.
Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.
Skeletal muscle exhibits an unusually complex architecture, in which large multinucleated myofibers accommodate a small population of resident muscle stem cells (MuSCs) along their surface. In addition, myofibers contain molecularly and functionally specialized domains at junctions with motor neurons and tendons. Regeneration of this tissue, therefore, requires a coordinated series of events, spanning MuSC activation, proliferation, fusion to restore myofiber mass, as well as reconstruction of specialized domains. Recent advances have begun to reveal how myogenic nuclei undergo dynamic state transitions in response to interactions with surrounding cell types, and how these states can be remodeled during regeneration. Here, we discuss emerging principles of myonuclear plasticity and spatial specialization.
The gastrointestinal tract possesses a remarkable regenerative capacity to maintain tissue homeostasis against various injuries. However, the intestine and stomach exhibit distinct regenerative strategies. In the intestine, damage to Lgr5-positive (Lgr5+) stem cells induces cellular plasticity and the emergence of transient Revival stem cells (RevSCs), a process critically dependent on YAP/TAZ signaling. Conversely, the stomach utilizes paligenosis, where quiescent p57-positive (p57+) mature chief cells act as reserve stem cells, dedifferentiating to restore damaged tissue. Although the cellular origins differ, both organs appear to share some common regenerative features, including transient activation of pro-proliferative programs such as YAP/TAZ signaling. In contrast, whether Retinoic Acid (RA) signaling also serves as a conserved mechanism for regenerative resolution in the stomach remains to be determined. In this review, we discuss the cellular and molecular mechanisms governing regeneration in these two organs. This comparative analysis provides a framework for future research.
Somatic variants accumulate in human brain cells throughout the lifespan. Variant allele fraction has traditionally been used as a proxy for both the developmental timing of somatic variants and their functional effect, based on the assumption that earlier mutations are shared by larger cell populations and therefore have greater potential for severe phenotypes. However, recent discoveries challenge this simplified model. Variables such as developmental bottlenecks, lineage restriction, and cellular and molecular context play critical roles in shaping the distribution and functional impact of somatic variants in the brain. These insights support a shift toward a context-dependent framework for interpreting somatic mosaicism.
Historically, the field of psychiatry has relied on descriptive categories, as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD). However, with increasing knowledge of molecular processes that contribute to mental disorders, the descriptive approach has been criticised. The current descriptive diagnostic categories lack sensitivity and specificity; as such, diagnostic heterogeneity remains a challenge for clinics and research. The search for more homogeneous patient groups is fuelled by both the molecular background, looking into molecular processes, pleiotropy, transdiagnostic, and diagnosis-specific markers, as well as from the phenotypic perspective. Immune-related molecular endophenotypes, as well as deep phenotyping, have been suggested as an approach to reduce the challenge of heterogeneity. This literature review focuses on functional immunogenomics, deep clinical phenotyping, and other approaches currently being discussed to resolve the burden of heterogeneity for mental disorders and provides a multidisciplinary perspective and roadmap towards reducing the impact of heterogeneity for research. With the current literature at hand, we provide evidence for the thesis that functional immunogenomics combined with deep clinical phenotyping offers a viable strategy to reduce the influence of heterogeneity.
This review integrates longitudinal transcriptomic and functional studies to examine how embryonically born neurons acquire their adult identities. Single-cell atlases reveal that in addition to gene expression changes, neuron types undergo shifts in subtype composition as they mature from nascent to mature identities. Shifts in subtype composition likely reflect the unique sequence of developmental events followed by each neuron and explain why, in some neuron types, functional diversity in adults is not fully explained by adult transcriptomics alone. Instead, adult neuronal identity is best understood as a culmination of transient and stable transcriptomic changes over time that are regulated by the combinatorial action of sequentially activated intrinsic and extrinsic factors. Which factors regulate transcriptional transitions in each neuron type, how trajectories are coordinated across functionally related neurons, how chromatin states accommodate temporal changes, and whether time itself is an important factor in determining adult identity, remain open questions.
Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.
An emerging concept across multiple adult tissues implies that regeneration involves the transient reactivation of developmental programs, rather than exclusively relying on the mobilization of dedicated multipotent adult stem cells. For glandular epithelia such as the ones forming the mammary, salivary, lacrimal, and prostatic glands, revisiting previous literature from this angle points to a convergence toward a similar model of fetal-like reversion in regeneration. Despite differences in embryonic origin, function, and branching morphology, the recurrent involvement of a molecular axis involving YAP, p63, and Notch signaling in the induction and resolution of epithelial plasticity highlights a high degree of pathway conservation. The primary scope of this short review is to critically re-evaluate existing literature under the conceptual framework of fetal-like reversion, aiming to highlight some developmental pathways that are re-utilized during the regeneration of glandular organs and to discuss the broader implications of these shared molecular mechanisms in the context of disease, namely cancer.
How progenitor lineage relationships shape the cellular diversity and organization of the human cortex remains a central question in developmental neuroscience. Lineage tracing provides a framework for understanding how developmental trajectories generate this diversity by capturing cellular history rather than static molecular identity, revealing progenitor fate potential, temporal regulation of developmental competence, and spatial patterns of clonal organization. In this review, we examine advances in prospective viral barcoding, clustered regularly interspaced short palindromic repeats (CRISPR)-based evolvable lineage recording, and retrospective inference from endogenous somatic mutations, highlighting how these complementary approaches are reshaping our understanding of human cortical development. We discuss evidence that human cortical progenitors exhibit expanded fate potential, prolonged temporal control of lineage output, and regionally patterned lineage dispersion, distinct from canonical rodent models. We further consider how integrating lineage information with molecular profiling and genetic perturbation enables causal dissection of developmental programs. Finally, we explore how disrupted lineage dynamics contribute to neurodevelopmental disorders, suggesting disease mechanisms as deviations in developmental trajectories. Recognizing lineage dynamics as an organizing principle will be essential for linking developmental ancestry to cortical organization and disease vulnerability.
Cell fate choice during development generates the large cell type diversity required to build the complex tissues and organs in our bodies. These cell fate decisions involve the cell-type-specific regulation of gene expression. At the chromatin level, this differential gene expression can be achieved by distinct strategies, which either involve changes in accessibility or solely differential transcription factor binding. In this review, we summarize these two strategies and their use during spatial and temporal patterning. We describe how the generation of cell type diversity in tissues can involve the integration of both strategies and discuss the implications for cell fate choice associated with each.
The mammalian telencephalon contains molecularly and functionally diverse inhibitory neuron subtypes that are essential for balanced neural circuit function and dynamics.The developmental process that generates this diversity from undifferentiated neuronal progenitor cells is governed by cis-regulatory elements (CREs) and the transcription factors (TFs) that bind to them. In combination with associated transcription co-regulators and epigenetic regulators, these transcription factors form gene regulatory networks that control the establishment of lineage-specific patterns of gene expression, thereby conferring each cell type its molecular identity.Numerous genetic variants associated with neurological and mental disorders affect proteins that act at CREs or alter their regulatory activity. Mapping risk gene expression onto adult cell taxonomies, however, often fails to reveal how neuronal circuits become dysfunctional. Emerging evidence supports a model in which genetic variation modulates developmental timing, fate bias, and lineage allocation. Such modulation affects how neurons adopt particular identities and often leads to imbalanced subtype proportions among otherwise normal cell types.In this review, we synthesize findings from developmental genetics, lineage tracing, and human disease to examine how regulatory mechanisms bias inhibitory neuron fate trajectories and how genetic risk reshapes these processes during development.
Early embryogenesis is driven by precisely regulated transcriptional programs that guide the transition from a fertilized zygote to a multicellular organism. This process proceeds through sequential phases, beginning with zygotic genome activation and progressing toward lineage specification. Disruptions to these programs can result in developmental defects or even embryonic lethality. Recent advances in multiomic technologies have revealed how developmental genes are regulated at layers of transcription factors, histone modifications, three-dimensional (3D) genome, and transposable elements. Here, we review recent progress on the mechanistic understanding of transcriptional regulation in early embryos and discuss their implications for fundamental principles of embryogenesis.
Directed induction of vascular regeneration and differentiation has significant clinical implications for the treatment of ischemic diseases and for the construction of functional, complex organoid models. The transcription factor ETS variant 2 (ETV2) has been identified in model organisms such as zebrafish and mice as a core regulator of embryonic angiogenesis, orchestrating vascular development by controlling endothelial cell (EC) differentiation. In recent years, in vitro studies have further revealed the multifaceted roles of ETV2. Beyond its essential function in embryonic vascular development, ETV2 can efficiently drive the differentiation or transdifferentiation of human pluripotent stem cells and somatic cells, such as fibroblasts, toward the endothelial lineage. These findings lay a theoretical basis for exploiting ETV2 in both vascular regenerative therapies and the in vitro generation of ECs. This review systematically summarizes the molecular mechanisms by which ETV2 governs endothelial fate specification during embryonic development, highlights current strategies for manipulating vascular cell differentiation in vitro, and discusses the major challenges associated with the translational application of ETV2-based cell engineering technologies.
Cell fate plasticity - the capacity of cells to transition between distinct identities - is particularly evident in pluripotent and totipotent cells, including embryonic cells and their in vitro stem cell counterparts. Accumulating evidence indicates that these cell states are accompanied by extensive remodeling of three-dimensional (3D) chromatin organization, including changes in compartments, topologically associating domains, and enhancer-promoter interactions. Engineering chromatin architecture to modulate pluripotency- or totipotency-associated genes has emerged as a promising strategy to reprogram cell identity and acquire pluripotent or totipotent features. Realizing this potential, however, requires a comprehensive understanding of both the universal principles of 3D chromatin regulation and the mechanisms specific to pluripotency or totipotency. Here, we review recent advances linking 3D chromatin structure to pluripotency and totipotency, and outline future directions for elucidating their regulatory logic. We also highlight key open questions that must be addressed to harness 3D genome engineering for controlling cell pluripotency or totipotency.
