Aug 2026· Open Biology· Vol 16 8· 0 citations· 205 references
Medicine
TL;DR
This review combines findings from airway, brain ventricles and Xenopus epidermal systems to reveal how mechanical cues may interact with transcriptional networks and cell cycle regulators during multiciliogenesis and suggests a model where mechanical forces serve as contextual regulators that enable, time and control the execution of the multiciliated differentiation programme.
Abstract
Multiciliated cells, through the coordinated beating of motile cilia, are vital for moving fluids in the brain and mucus in the airways and in the reproductive organs. Their dysfunction leads to diseases, associated with chronic airway infections, subfertility and ventricular enlargement. A group of transcription factors and a cell cycle variant enable the differentiation of multiciliated cells. However, how the multiciliated differentiation programme is initiated, timed and spatially regulated within developing tissues remains unclear. In this review, we combine findings from airway, brain ventricles and Xenopus epidermal systems to reveal how mechanical cues may interact with transcriptional networks and cell cycle regulators during multiciliogenesis. We suggest a model where mechanical forces serve as contextual regulators that enable, time and control the execution of the multiciliated differentiation programme.
Across multicellular life, cells need to act in a coordinated manner to generate tissues with specific and reproducible forms necessary for their effective function. This process of morphogenesis is regulated by a myriad of signalling and mechanical inputs, which are often inter-related. Tissue morphogenesis typically occurs within constrained environments, such as the eggshell or buds for plants, that often have complex geometries. Yet, understanding how such boundaries impact the formation of tissues and organs has remained challenging. Recent advances in imaging, in vitro methods and genetic manipulation are leading to new understanding of how geometry interplays with signalling and mechanics to ensure tissues form robustly. Here, we focus on the role of geometric constraints in guiding morphogenesis, utilising examples from across the animal and plant kingdoms to highlight key principles. This demonstrates that geometry can be instructive, rather than simply a passive constraint, during morphogenesis.
R. Harrison, Olivier Hamant, T. Saunders· Development· 0 citations
Gastrulation is thought to be driven primarily by forces generated within individual cells. These cell-intrinsic forces collectively induce tissue-scale flows and transform the monolayered embryo into a multilayered structure. However, as the embryo constitutes a mechanically closed system, these flows must be balanced by regions of resistance or anchoring to enable asymmetric morphogenesis. In the Drosophila embryo, integrin-mediated attachment of the blastoderm to the vitelline envelope has been shown to stabilize germ band extension at the organismal scale. Disrupting such an attachment leads to a characteristic twisting phenotype. Yet, how this attachment shapes concurrent global morphogenetic events remains unclear. We discovered that the integrin α-subunit scab, which mediates the attachment, is expressed in three different regions of the cellular blastoderm near prominent invagination events. Through a combination of light-sheet imaging, genetic and mechanical perturbations, we demonstrate that integrin-enhanced friction is essential for unidirectional tissue flows in those regions, with effects including cephalic furrow positioning and epithelial stability. Guided by a minimal physical model, we further show that multiple attachment sites enhance the robustness and reproducibility of global tissue movements. Together, our results indicate that Drosophila gastrulation emerges from a balance between cell-intrinsic force generation and spatially distributed adhesion to the surrounding envelope, which together shape tissue flows at the embryo scale.
Marina B. Cuenca, W. Yau, Giulia Serafini et al.· bioRxiv· 0 citations
The morphogenesis of developing tissues relies on extensive cellular rearrangements in shape, position, and identity. A key process in reshaping tissues is cell intercalation-driven elongation, where epithelial cells align and intercalate along a common axis. Typically, analyses focus on how peripheral cortical forces influence cell shape changes. Less attention is given to how inhomogeneities in internal structures, particularly the nucleus, impact cell shaping. Here, we examine how pulsed contractile and extension dynamics interact with the nucleus in elongating Drosophila embryos. Our data show that tightly packed nuclei in apical layers hinder tissue remodeling/oscillatory behaviors. We identify two mechanisms for resolving internuclear tensions: nuclear deformation and dispersion. Embryos with non-deformable nuclei use nuclear dispersion to maintain near-normal extensile rates, while those with non-dispersible nuclei due to microtubule inhibition exhibit disruptions in contractile behaviors. Disrupting both mechanisms leads to severe tissue extension defects and cell extrusion. These findings highlight the critical role of nuclear shape and positioning in the topological remodeling of epithelia.
To further understand how nuclear dispersion along the apical-basal axis is regulated during the germband extension (GBE), we examined the structural reorganization of microtubule (MT) arrays over time. We find that the initial centrosome-derived MT network, which forms an inverted basket-like structure surrounding the nucleus, transitions into non-centrosomal MT (ncMT) arrays enriched at the apical cortex as GBE progresses. Disruption of Patronin, a minus-end tracking proteins (-TIP), impaired both perinuclear and apical MT pools, while inducing ectopic MT accumulation at centrosomes. This led to a failure in nuclear dispersion, with nuclei remaining densely packed in the apical domain. Patronin inhibition also reduced the proportion of nuclei undergoing active displacement and significantly slowed nuclear migration. Inhibiting CLASP, a plus-end tracking protein (+TIP), produced a similar disruption in MT organization, with even greater centrosomal enrichment. CLASP loss resulted in a striking reduction in the number of actively dispersing nuclei, disrupted apical-basal nuclear orientation and impaired nuclear anchoring to the apical cortex. Detailed examination of centrosomal MT enrichment in CLASP- and Patronin-depleted embryos revealed a competitive relationship between centrosomal and non-centrosomal MT populations, suggesting an antagonistic regulatory mechanism. We also observed compensatory interactions between γ-tubulin and patronin at centrosomes: γ-tubulin inhibition led to increased Patronin levels and enhanced total MT abundance, with only mild effects on nuclear dispersion. Finally, perturbation of EB1 disrupted the apical shift of the MT basket and impaired nuclear anchoring to the cortex, although apical-basal nuclear orientation was largely preserved. Together, these findings highlight the importance of properly organized and dynamically remodeled MT networks – particularly the transition from centrosomal to non-centrosomal arrays – for accurate nuclear positioning, orientation, and dispersion during epithelial tissue remodeling.
The respiratory system of Drosophila melanogaster consists of a network of interconnected gas-filled epithelial tubes. Stellate-shaped terminal cells at the termini of each tracheal branch serve as the primary source of oxygen and grow continuously throughout larval stages in response to hypoxic signals. Each cytoplasmic branch of a terminal cell hollows out to form subcellular seamless tubes that lack epithelial junctions. It is known that over the course of larval development, tracheal terminal cells grow by extending new branches and lengthening existing branches. By the end of larval development, each branch of these highly ramified cells contains a subcellular lumen; the relationship between branch and tube extension over this period of immense growth has yet to be explored. Here we demonstrate that branch extension and intracellular lumen formation are spatially and temporally coupled throughout larval stages, however, nascent tubes formed during a larval instar are fluid-filled and do not inflate with air until the following molt. This has interesting implications for the delivery of oxygen to target tissues during the first 48 hours of larval growth.
T. Simpson, Jodi Schottenfeld-Roames· Developmental Biology· 0 citations
Cell migration is a fundamental biological process required for embryonic development, tissue repair, immune surveillance, and cancer metastasis. To successfully navigate the diverse mechanical environments encountered in vivo, cells exhibit migratory plasticity, the ability to dynamically alter their migration strategy in response to extracellular matrix architecture and mechanics. Distinct migration modes employ unique force-generating mechanisms that require extensive reorganization of the cytoskeleton, intracellular architecture, and cellular energetics. Understanding how cells coordinate these adaptations remains a central question in cell biology. The first chapter provides the conceptual framework for this work by reviewing the mechanisms that govern cell migration in three-dimensional (3D) environments. Particular emphasis is placed on migratory plasticity, the ability of cells to transition between distinct migration strategies in response to extracellular matrix architecture and mechanics. This chapter discusses how changes in cell-ECM adhesion, actomyosin contractility, intracellular pressure, and cytoskeletal organization enable cells to navigate diverse tissue environments. It also examines the emerging role of mitochondria in cell migration, highlighting how mitochondrial positioning and function are coordinated with localized energetic demands and identifying important gaps in our understanding of how mitochondrial organization is regulated during 3D migration. The second chapter explores how these distinct mechanical programs influence mitochondrial organization. Because mitochondria are dynamically positioned to meet localized energetic demands, I investigated mitochondrial distribution, dynamics, and membrane potential during fibroblast migration through mechanically distinct 3D environments. Using cell-derived matrices (CDMs), which promote nuclear piston migration, and collagen I matrices, which support lamellipodial migration, I demonstrate that matrix mechanics drive the formation of spatially distinct mitochondrial populations with unique organizational and functional properties. During nuclear piston migration, mitochondria become enriched within a specialized anterior perinuclear compartment characterized by elevated membrane potential and reduced organelle motility. Disruption of the contractile machinery responsible for nuclear pulling abolishes this anterior energetic compartment, demonstrating that matrix mechanics coordinate mitochondrial organization with the force-generating mechanisms of migration. Finally, this dissertation investigates the cytoskeletal architecture responsible for transmitting force during nuclear piston migration. While previous work established that vimentin intermediate filaments connect the nucleus to the cytoskeleton through Nesprin-3, this work identifies plectin as the mechanosensitive cytolinker that couples vimentin intermediate filaments to the actomyosin cytoskeleton. These findings establish the molecular linkage that enables actomyosin-generated forces to be transmitted to the nucleus during pressure-driven migration and provide a mechanistic framework for understanding nuclear force transmission in confined 3D environments. Together, this work demonstrates that extracellular matrix mechanics regulate both the mechanical and energetic organization of migrating cells through migratory plasticity. By integrating cytoskeletal force transmission with mitochondrial compartmentalization, these studies provide new insight into how cells coordinate intracellular architecture to support efficient migration through complex three-dimensional tissues.
The regulation of epithelial cell shape is fundamental to development, homeostasis and disease, and is intricately linked to tissue function. Epithelial morphology emerges from integration of biochemical and mechanical cues across multiple scales, from intrinsic cellular factors to tissue-wide forces. In this review we focus on the mechanical aspects of cell shape control and highlight the multi-scale regulation of epithelial cell shape that links (i) cell-intrinsic factors, such as cytoskeletal organization, contractility and growth, (ii) the local mechanical environment, including cell-matrix interactions and (iii) tissue-scale mechanics governing global morphogenesis. At the cellular level, contractility and growth generate stresses that interact with the surrounding microenvironment, shaped by the extracellular matrix. At the tissue level, large-scale stresses and boundary constraints from neighbouring tissues, bones or cuticles further shape epithelial morphology. Feedback across scales ensures robustness and adaptability of epithelial architecture. In this review, we synthesis recent insights into the mechanical control of epithelial cell-shape transitions and how intrinsic and extrinsic stresses integrate to drive morphogenesis. We also highlight how theoretical modelling frameworks are increasingly essential for disentangling the multiscale interplay of forces that govern epithelial architecture. This review aims to provide perspectives on how epithelial mechanics are coordinated by multiscale regulation and how they contribute to development, homeostasis and disease.
Jianyi Mai, Abhirami Anil Gayathry, D. Richards et al.· Seminars in Cell and Develop...· 0 citations
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