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Invagination

Invagination is the process by which a portion of a surface or layer folds inward upon itself to form a cavity, pouch, groove, or tube, enabling the creation of more complex structures.^[1] In biology, this is a fundamental morphogenetic process, typically involving an epithelial sheet, and is essential during embryonic development, where it drives tissue remodeling and organ formation across diverse organisms, from invertebrates like sea urchins to vertebrates including humans.^[2] In developmental biology, invagination plays a central role in gastrulation and subsequent stages, ensuring proper patterning and compartmentalization of embryonic tissues, with disruptions potentially leading to congenital defects such as neural tube disorders.^[3] The mechanisms underlying invagination involve coordinated cellular and extracellular forces, including apical constriction driven by actomyosin contractility.^[4] Other modes include canopy contraction, cell-on-cell migration, and extracellular matrix remodeling. Recent studies highlight how patterned contractile cells prevent mechanical instabilities during tissue folding, ensuring stable morphogenesis.^[5] Beyond embryology, invagination describes normal anatomical features, such as gastric pits in the stomach lining. In pathology, abnormal invagination can manifest as intussusception, where one segment of the intestine telescopes into an adjacent segment, often due to a lead point like a polyp, leading to obstruction and ischemia, particularly in children under five years old and requiring urgent intervention.^[6] The term invagination is also used in other disciplines, such as geology to describe deep depressions in rock strata or basins, and in materials science for designing structures with controlled folding.^[7]

Biological Invagination

Definition and Process

Invagination is a fundamental morphogenetic process in developmental biology, characterized by the inward folding or infolding of a layer of cells, typically an epithelial sheet, to form a cavity, pouch, or tube-like structure during embryogenesis.^[8] This process involves the localized buckling or warping of the cell layer, creating internalized pockets or crypts that contribute to tissue shaping and patterning.^[1] Primarily observed in epithelial tissues, invagination enables the reorganization of cell sheets to generate three-dimensional structures essential for organ formation.^[9] The general process of invagination begins with the initial puckering or flattening of the tissue surface at a specific site, driven by coordinated changes in cell positions and adhesions.^[8] This is followed by the inward movement of the cell layer as a cohesive sheet, where cells bend toward the interior, forming a pit or depression that deepens progressively.^[10] The process culminates in the stabilization of the folded structure, often resulting in the creation of internalized tubes or cavities, such as those that will develop into primitive gut or neural precursors.^[9] Throughout, the epithelial integrity is maintained, distinguishing it from movements involving cell dissociation. Invagination differs from related morphogenetic processes, such as evagination, which involves the outward folding of a cell layer away from a cavity, as seen in the apical protrusion of tissues.^[9] In contrast to ingression, where individual cells detach and migrate inward independently, invagination occurs as a collective sheet movement without loss of cell-cell contacts.^[11] It also contrasts with epiboly, a spreading or thinning of epithelial sheets over other cells to enclose the embryo, rather than forming an inward pocket.^[9] This process is evolutionarily conserved across metazoans, serving as a key mechanism for tissue internalization in diverse animal lineages from cnidarians to bilaterians.^[12] The conservation extends to the underlying genetic regulatory networks that orchestrate invagination during gastrulation in protostomes, deuterostomes, and non-bilaterian animals.^[13]

Role in Development

Invagination plays a pivotal role in gastrulation by facilitating the internalization of presumptive endoderm and mesoderm cells from the epiblast, thereby establishing the three primary germ layers essential for embryonic patterning. During this process, internalization occurs through mechanisms such as involution and ingression at the primitive streak in vertebrates or invagination of epithelial sheets at sites like the ventral furrow in invertebrates, allowing mesodermal and endodermal progenitors to ingress and displace the blastocoel, which sets the foundation for trilaminar organization. This internalization is crucial for separating the germ layers and positioning them to undergo subsequent differentiation into tissues and organs.^[14]^[15] In organogenesis, invagination-driven folding contributes to the formation of key structures, including the archenteron, which emerges as an endodermal invagination during gastrulation and elongates to form the primitive gut in many species. Similarly, primary neurulation involves the invagination of the neural plate, where midline cells constrict apically to initiate folding, leading to the enclosure of the neural tube that gives rise to the central nervous system. Paraxial mesoderm precursors are internalized during gastrulation (via involution and ingression in vertebrates), with somites subsequently forming through segmentation and epithelialization of the presomitic mesoderm, which differentiate into structures such as vertebrae, muscles, and dermis. These processes highlight invagination's role in generating topological complexity and compartmentalization necessary for organ development.^[16]^[17] Invagination integrates with other morphogenetic movements, such as convergence-extension and involution, to establish the overall body plan by coordinating cell rearrangements across the embryo. Convergence-extension narrows and elongates tissues post-invagination, while involution rolls cells over the lip of the invaginating region, ensuring efficient germ layer deployment and axial elongation. This orchestration prevents defects in body axis formation and supports the transition from a spherical blastula to an elongated embryo.^[18]^[19]^[15] The timing and regulation of invagination depend on conserved signaling pathways, including BMP, Wnt, and FGF, which initiate and specify sites of folding. BMP signaling promotes apical constriction and epithelial invagination by regulating actin dynamics and cell shape changes at presumptive sites. Wnt pathways coordinate planar cell polarity and convergence, ensuring precise invagination initiation, while FGF signals integrate with these to modulate proliferation and migration, thereby controlling the spatial and temporal onset of the process. Disruptions in these pathways can lead to failures in germ layer formation and organ patterning.^[20]^[21]^[22]

Historical Development

Early Observations

The earliest systematic observations of invagination emerged in the early 19th century as part of the shift from preformationist views to epigenesis in embryology. Christian Heinrich Pander, in his 1817 studies on chick embryos, first described the formation of the three primary germ layers—ectoderm, mesoderm, and endoderm—through dynamic tissue rearrangements during gastrulation, including the inward folding of epithelial sheets that would later be recognized as invagination.^[23] This work laid the groundwork for understanding invagination as a key process in establishing embryonic body plans, though Pander focused primarily on the chick's primitive streak rather than explicit cellular folding.^[24] Karl Ernst von Baer extended these insights in his comprehensive 1828–1837 treatise on vertebrate embryology, documenting invagination during gastrulation in amphibian embryos, where presumptive endodermal cells fold inward at the blastopore to form the archenteron.^[25] Von Baer's observations across species, including chicks and frogs, highlighted the conserved role of such epithelial invaginations in generating germ layers and organizing the embryo's dorsoventral axis, emphasizing similarities among vertebrate early stages before divergence into species-specific forms.^[24] These descriptions relied on careful dissection and early optical aids, revealing invagination as a morphological transition from the blastula to the gastrula without yet exploring underlying causes.^[26] By the mid-19th century, advances in light microscopy enabled more detailed examinations of invagination. Wilhelm Roux, in his 1880s investigations of frog embryos, used improved microscopes to observe epithelial folding and cell movements during gastrulation, providing evidence of coordinated sheet invagination that contributed to mesoderm internalization.^[27] Similar microscopic studies on sea urchin embryos, conducted by Roux and contemporaries like Alexander Agassiz, revealed primary invagination of vegetal cells forming the gut rudiment, underscoring the process's prevalence across deuterostomes.^[28] The term "invagination" gained prominence in this context around the 1870s, notably through Ernst Haeckel's gastraea theory, which formalized it as the inward buckling of the blastula wall to produce the two-layered gastrula.^[29] These early observations, while groundbreaking, were inherently limited by their reliance on descriptive anatomy and static imaging techniques, offering no insights into molecular regulators or dynamic cellular forces driving invagination.^[30] Pre-1950 embryology thus remained phenomenological, cataloging morphological changes without experimental perturbation or biochemical analysis, setting the stage for later mechanistic inquiries.^[31]

Key Advances and Models

In the mid-20th century, pioneering experiments by Hans Spemann and Hilde Mangold utilized transplantation techniques to elucidate invagination's inductive role in embryonic development. By grafting the dorsal blastopore lip from one amphibian gastrula to another, they induced a secondary axis, demonstrating that invaginating tissues act as organizers that signal surrounding cells to form neural structures, a discovery foundational to understanding tissue interactions during folding.^[32] Complementary use of vital dyes in fate-mapping studies around this period further traced cell movements during invagination, confirming its centrality in germ layer formation.^[33] The molecular era from the 1980s onward shifted focus to genetic mechanisms underlying invagination through large-scale screens in model organisms like Drosophila. Christiane Nüsslein-Volhard and Eric Wieschaus identified key zygotic genes such as snail and twist in their 1979–1980 mutagenesis screens, revealing their essential roles in ventral furrow formation and mesoderm invagination; mutants lacking these genes failed to undergo proper epithelial bending, highlighting transcriptional regulation of cell shape changes. These findings, built upon by subsequent analyses, established a genetic framework linking dorsal-ventral patterning to invaginating morphogenesis.^[34] Post-2010 advances integrated live imaging, optogenetics, and computational simulations to uncover dynamic force generation in invagination. High-resolution confocal microscopy and light-sheet imaging enabled real-time visualization of actomyosin contractility during Drosophila ventral furrow formation, showing pulsed apical constrictions drive tissue bending.^[35] Optogenetic tools, such as light-activated myosin inhibitors, demonstrated mechanical bistability in epithelial sheets, where reversible actomyosin inhibition toggles between flat and invaginated states, revealing feedback between contractility and geometry.^[36] Recent 2023–2025 studies further detailed mechanical instability prevention; for instance, the cephalic furrow in fly embryos acts as a patterned invagination that absorbs compressive stresses at the head-trunk boundary, averting buckling during gastrulation, as shown through laser ablation and finite element analysis.^[5] Additional 2025 research revealed bidirectional translocation of actomyosin networks as a central driver of epithelial invagination in Drosophila, integrating apical and basal dynamics.^[37] Concurrently, hydromechanical models propose that osmotic pressure gradients and fluid incompressibility facilitate transitions between invagination and evagination in closed epithelial systems, integrating biophysical principles with observed dynamics.^[38] Theoretical modeling has paralleled these experimental strides, with vertex and finite element approaches simulating tissue-level bending. Odell et al.'s 1981 vertex model treated epithelial cells as polygonal units with contractile boundaries, predicting how differential tensions induce folding akin to neural plate invagination in vertebrates. Updated in 2025, PLOS Computational Biology simulations extended this to 3D deformable cell-based frameworks, incorporating volume conservation and adhesion to replicate gastrulation invaginations driven by mechanical properties alone, without predefined forces.^[39] These models underscore invagination as an emergent property of cellular mechanics, informing predictions across species.

Mechanisms of Invagination

Apical Constriction and Supracellular Cables

Apical constriction involves the progressive reduction in the apical surface area of epithelial cells, driven by actomyosin contractility, which transforms columnar cells into wedge- or bottle-shaped forms to promote tissue bending and invagination.^[40] This process generates internal forces that narrow the cell apex while the basal surface remains relatively unchanged, creating a wedge geometry that collectively folds epithelial sheets during morphogenesis.^[41] Actomyosin contractility arises from the interaction of non-muscle myosin II motors with actin filaments, organized into pulsed or pulsatile networks that exert tangential forces along the apical cortex.^[40] The primary molecular regulators of apical constriction include the RhoA/ROCK signaling pathway, where activated RhoA GTPase recruits and stimulates Rho-associated kinase (ROCK), which in turn phosphorylates the regulatory light chain of myosin II to enhance its ATPase activity and promote actin-myosin filament assembly.^[42] This phosphorylation increases the contractility of the apical actomyosin network, enabling sustained force generation necessary for area reduction.^[43] Upstream signals, such as those from G-protein-coupled receptors or integrins, spatially pattern RhoA activation to ensure coordinated constriction across cell populations.^[40] Supracellular actomyosin cables emerge as aligned arrays of myosin II and F-actin filaments spanning multiple cells, typically anchored at adherens junctions via cadherin complexes, to synchronize contractility and drive uniform tissue puckering during invagination.^[44] These cables form through anisotropic recruitment of myosin, facilitated by planar cell polarity cues and junctional proteins like Zasp52, which stabilize the supracellular alignment and transmit tension across cell boundaries.^[45] By contracting as a cohesive unit, they amplify local forces to initiate and propagate bending, preventing uncoordinated deformations.^[46] Quantitative modeling of apical constriction often employs viscoelastic frameworks to describe force balance, where contractile stresses counteract elastic and viscous resistances in the tissue. In simplified linear viscoelastic models, the generated stress \sigma balances the product of tissue stiffness k and relative apical area change \Delta A / A_0, approximated as:

\sigma \approx k \cdot \frac{\Delta A}{A_0}

where A_0 is the initial apical area. This relation derives from the mechanical equilibrium equation for a Kelvin-Voigt material under quasi-static conditions, incorporating active stress from actomyosin as a perturbation to passive viscoelastic responses, with k reflecting Young's modulus scaled by geometric factors.^[47] Such models predict that constriction rates depend on myosin density and calcium-mediated activation, with typical stresses on the order of 100–250 Pa sufficient to achieve observed area reductions of 50–80% in epithelial sheets.^[47]^[48]

Cell Shape Changes and Telescoping

In epithelial invagination, basal relaxation plays a key role in facilitating inward folding by allowing expansion of the basal cell surfaces and adjustments in cell height, often without relying on pronounced apical constriction. This process involves the downregulation of basal myosin-II activity, which reduces contractile forces at the cell base and enables cells to elongate vertically during early stages of tissue bending. For instance, in Drosophila gastrulation, basal myosin-II downregulation prior to invagination promotes cell lengthening from approximately 25 μm to 40 μm, releasing stored elastic energy that drives initial tissue curvature. Later, further relaxation allows cell shortening to about 26 μm, aiding furrow closure and completing the invagination. This mechanism ensures volume conservation and coordinated shape changes across the epithelium, contrasting with more force-dependent apical processes. The telescoping mechanism represents a coordinated form of vertical intercalation, where cells slide or stack inward relative to their neighbors, generating invagination through geometric rearrangement rather than primary contraction. Observed in mammalian salivary glands and early tooth development, this involves peripheral columnar epithelial cells migrating upward and tilting outward via centripetal apical protrusions, effectively "telescoping" the tissue inward. Three-dimensional imaging reveals that cell tilt angles correlate directly with the depth of invagination, with the process being autonomous to the epithelium and dependent on actin cytoskeleton dynamics, as inhibition by cytochalasin D or CK666 disrupts protrusion formation. Signaling pathways such as Sonic Hedgehog (Shh) and FGF are essential for orienting these protrusions, highlighting the mechanism's reliance on directed cell motility for pocket formation. Canopy contraction and basal wedging contribute to invagination by inducing localized geometric distortions through superficial layer dynamics. In this process, suprabasal cells undergo horizontal contraction via intercalation, forming a shrinking and thickening "canopy" that exerts extrinsic forces on underlying basal cells, causing them to adopt wedge-like shapes and facilitating pocket invagination. This is evident in ectodermal placodes, where peripheral basal cells, anchored to the basal lamina, extend apically to transmit tension via E-cadherin junctions, enabling rapid bending (e.g., 40° in 150 seconds). The mechanism is conserved across skin appendages like teeth and hair follicles, with actomyosin contractility propagating forces tissue-wide, though it is more prominent in later budding stages rather than initial invagination in hollow structures like salivary glands. Biophysical models of these shape changes often employ elasticity theory to describe cell-level deformations, treating epithelial layers as thin sheets subject to bending and stretching. A key parameter is the bending modulus \kappa, which quantifies resistance to curvature and is given by the formula for thin plates:

\kappa = \frac{E h^3}{12(1 - \nu^2)}

where E is the Young's modulus, h is the sheet thickness, and \nu is the Poisson's ratio. This modulus governs how basal relaxation and wedging alter tissue curvature, with higher \kappa values stabilizing folds against buckling during telescoping or canopy-driven deformations. Such models predict that coordinated height changes and intercalation minimize energy costs, enabling efficient invagination in response to tension gradients.

Examples in Embryonic Development

Invertebrate Gastrulation

In invertebrate gastrulation, invagination serves as a primary mechanism for internalizing presumptive mesodermal and endodermal tissues, establishing the basic body plan. A prominent example occurs in the fruit fly Drosophila melanogaster, where the ventral furrow forms through coordinated apical constriction of presumptive mesodermal cells in the ventral blastoderm. These cells, numbering approximately 1,000, undergo progressive narrowing of their apical surfaces driven by actomyosin contractility, transforming from columnar to wedge-shaped and generating tissue curvature that folds the epithelium inward to form a transient tube. This process internalizes the mesoderm, positioning it beneath the ectoderm for subsequent delamination and migration.^[49] In the sea urchin (Strongylocentrotus purpuratus and related species), gastrulation initiates with primary invagination of the vegetal plate, a monolayered epithelium of about 200-300 cells that buckles inward to form the archenteron, the precursor to the digestive tract. This phase involves apicobasal shortening and changes in cell adhesion, creating a stub-like invagination without initial cell intercalation.^[50] Secondary invagination follows, elongating the archenteron through convergent extension and traction forces exerted by filopodia extended from secondary mesenchyme cells at the tip, which attach to the blastocoel roof and pull the structure toward the animal pole. These filopodia, composed of actin bundles, integrate mechanical tension to achieve tripling of the archenteron length.^[50] Comparative analysis reveals conserved reliance on apical constriction for initial folding in both systems, yet distinct temporal dynamics and force integration highlight evolutionary adaptations. In Drosophila, ventral furrow invagination begins around 3 hours post-fertilization and completes within 45 minutes, enabling rapid, synchronous internalization across the embryo's length via supracellular actomyosin cables. In contrast, sea urchin primary invagination initiates later, around 36-48 hours post-fertilization at 12-15°C, but proceeds more swiftly over approximately 30 minutes, followed by slower secondary elongation spanning hours, where filopodial pulling supplements intrinsic epithelial forces for directed extension. These differences reflect varying embryo sizes and developmental strategies, with Drosophila emphasizing speed for syncytial-to-cellular transitions and sea urchins prioritizing precise spatial guidance in a fluid-filled blastocoel.^[49]^[50] Experimental evidence from genetic perturbations underscores the essential role of regulatory genes in these processes. In Drosophila twist mutants, lacking the bHLH transcription factor Twist, presumptive mesodermal cells fail to undergo apical constriction, resulting in flattened ventral epithelium and complete arrest of furrow invagination, as Twist activates downstream targets like snail for mesoderm specification and morphogenesis. Similar disruptions occur in snail mutants, confirming a genetic cascade that couples signaling to mechanical execution, though partial internalization can occur via residual forces in hypomorphic alleles. These studies demonstrate invagination's sensitivity to transcriptional control, providing insights into conserved developmental robustness across invertebrates.

Vertebrate and Chordate Formation

In vertebrates, neural tube formation occurs through primary neurulation, a process involving the invagination of the neural plate to generate the central nervous system precursor. The neural plate, induced by signals from the underlying dorsal mesoderm, consists of elongated columnar cells that thicken and form a midline furrow at the medial hinge point, where cells adopt a wedge shape and anchor to the notochord, facilitating bending.^[16] This is followed by the elevation and convergence of the lateral neural folds toward the midline, driven by cytoskeletal changes and extracellular matrix remodeling, ultimately leading to their fusion and enclosure of the neural tube; in amphibians like Xenopus and mammals, this initiates at multiple anterior-posterior sites, contrasting with the more uniform progression in simpler chordates.^[16] The resulting tube differentiates into the brain and spinal cord, highlighting invagination's role in establishing bilateral symmetry and axial structures.^[16] In the cephalochordate Amphioxus (Branchiostoma), gastrulation proceeds via a straightforward invagination of the archenteron without the formation of specialized bottle cells, beginning at the blastula's equator with a wide blastopore where Wnt8 is expressed.^[51] Presumptive endoderm cells ingress to form the archenteron roof, which expands dorsally to contact the overlying ectoderm, inducing notochord and other axial structures through Nodal signaling and left-right asymmetric gene expression (e.g., lefty and nodal).^[51] This simple mechanism lacks the extensive cytoplasmic rearrangements and involution seen in vertebrates, relying instead on cortical cytoskeleton dynamics for cell movements, and results in a straightforward germ layer organization without pronounced mesodermal migration.^[51] Tunicate gastrulation, exemplified in the ascidian Ciona intestinalis, features endoderm invagination as the primary morphogenetic event, forming a cup-shaped archenteron driven by myosin II-mediated constriction in two sequential phases.^[52] Initially, apical constriction occurs in the vegetal-most endoderm cells via RhoA/Rho-kinase accumulation of myosin II at their apical surfaces, reducing cell height and initiating invagination around 5 hours post-fertilization.^[52] This transitions to collared rounding, where cells shorten apico-basally and expand laterally with myosin II redistributing to basal and lateral junctions, an endoderm-intrinsic process independent of adjacent germ layers and regulated by Nodal and Eph signaling relays.^[52] Evolutionarily, the transition from simple invagination in Amphioxus to the multi-step, involution-heavy gastrulation in vertebrates reflects adaptations for enhanced anteroposterior axial organization and head mesoderm development.^[53] In Amphioxus, minimal mesodermal involution allows overlapping expression of dorsal genes like goosecoid and brachyury, whereas vertebrates segregate these along the axis via Wnt/β-catenin signaling and convergent extension, enabling complex neural and somitic structures.^[53] Experimental suppression of involution in Xenopus embryos recapitulates Amphioxus-like patterns, underscoring how increased cell migration and polarization in vertebrates drove the elaboration of invagination for chordate diversification.^[53]

Other Biological Applications

Pathological Invaginations

Pathological invaginations refer to abnormal infoldings of tissues that deviate from normal developmental processes, often leading to clinical complications in various organ systems. These anomalies can arise from genetic, inflammatory, or mechanical factors and may result in obstruction, infection, or tissue damage if untreated. In medical contexts, they are distinguished from physiological invaginations by their association with disease states and the need for intervention. Intestinal intussusception represents a classic example of pathological invagination in the gastrointestinal tract, where one segment of the bowel telescopes into an adjacent segment, primarily affecting children under two years of age. This condition is the most common cause of intestinal obstruction in this demographic, with an incidence of approximately 20 to 100 cases per 100,000 children under 3 years of age annually in the United States.^[54] While over 90% of pediatric cases are idiopathic, often linked to lymphoid hyperplasia following viral infections, about 5% involve pathological lead points such as Meckel's diverticulum or tumors. Untreated, it can lead to bowel ischemia, perforation, and sepsis due to compromised blood supply. Therapeutic interventions typically begin with non-surgical reduction via air or hydrostatic enema, achieving success in 80-95% of cases, while refractory instances require surgical reduction to prevent recurrence, which occurs in 10-20% of patients. In dentistry, dens invaginatus, also known as dens in dente, is a developmental anomaly characterized by an infolding of the enamel organ into the dental papilla, creating a complex internal structure prone to pulp exposure and cyst formation. This condition most commonly affects permanent maxillary lateral incisors and premolars, with a prevalence of 0.3-10% in various populations. The widely adopted classification by Oehlers (1957) delineates three types based on invagination extent: Type I (enamel-lined invagination within the crown), Type II (invagination extending into the root but remaining within the tooth), and Type III (invagination penetrating through the root to communicate with the periodontal ligament, often forming periapical cysts). Consequences include early caries, pulpitis, and abscesses due to bacterial ingress. Endodontic treatment is the primary intervention, involving sealing the invagination with materials like mineral trioxide aggregate and root canal therapy for affected pulp, with success rates exceeding 80% when diagnosed early via radiography. Adenomyosis exemplifies pathological invagination in the female reproductive system, involving the ectopic invagination of endometrial tissue into the myometrium, resulting in uterine enlargement and dysfunctional bleeding. This condition shares pathophysiological similarities with endometriosis, affecting 20-35% of women with heavy menstrual bleeding, and is hypothesized to stem from basal endometrial gland penetration facilitated by trauma or hormonal influences. Recent advancements in 2025 spatial transcriptomics have elucidated the progression from initial invaginating sites to deep lesions, revealing upregulated genes in epithelial-mesenchymal transition and inflammatory pathways that drive ectopic endometrial penetration and fibrosis. These molecular insights highlight lesion heterogeneity, with invaginated regions showing distinct transcriptional profiles compared to surrounding myometrium, aiding in targeted diagnostics. While conservative management includes hormonal therapies, severe cases may necessitate hysterectomy, underscoring the need for early imaging like MRI to assess invagination depth.

Synaptic and Cellular Structures

In ribbon synapses of retinal photoreceptors, synaptic invaginations form elaborate tripartite structures where processes from horizontal and bipolar cells deeply embed into the photoreceptor terminal, facilitating multivesicular release and signal integration for visual processing.^[55] These invaginations surround the synaptic ribbon, a protein scaffold that tethers vesicles for rapid, sustained neurotransmitter release, enabling high-fidelity transmission in response to light changes.^[56] A 2022 study revealed species-specific patterns: primate rod spherules exhibit more branched invaginating processes and longer arciform densities compared to rodents, providing an expanded bipolar cell-rod synapse interface that enhances synaptic efficacy.^[57] The functional roles of these invaginations include optimizing synaptic efficacy by increasing the postsynaptic contact area and supporting rapid neurotransmission through efficient vesicle docking and fusion at the active zone.^[58] In photoreceptors, this architecture allows for continuous glutamate release modulated by light, contrasting with conventional synapses and underscoring adaptations for sensory transduction.^[59] In plant guard cells, analogous invaginations occur as tonoplast foldings and plasma membrane invaginations during stomatal closure, where cytoplasmic invagination into the vacuole reduces volume and promotes cell deflation to form the pore structure for gas exchange regulation.^[60] This process mirrors animal cell folding but is driven by osmotic stress and turgor changes.^[61] Beyond synapses, invaginations drive endocytosis, as in clathrin-mediated uptake where the plasma membrane invaginates to form coated pits for cargo internalization, a conserved mechanism across eukaryotes essential for receptor trafficking and nutrient acquisition.^[62] In gland formation, such as mammalian salivary glands, epithelial invagination proceeds via a vertical telescoping mechanism, where peripheral cells slide over central ones to initiate budding without apical constriction.^[63] This telescoping, briefly, integrates cell rearrangement for tissue folding in non-embryonic contexts.^[41]

Invagination in Other Disciplines

Geology

In geology, the term invagination is rarely used and specifically describes a deep depression of strata. This usage was employed by Donald L. Baars in his 2000 book The Colorado Plateau: A Geologic History to refer to such structural features.^[64] Unlike the active, cellular-driven processes in biology, geological depressions form passively through tectonic forces, such as compression in fold-thrust belts leading to buckling and shortening of rock layers. Such features can arise from plate convergence, which thickens the crust and causes deformation along faults and folds under brittle-ductile conditions in the lithosphere. Geologists study these structures using seismic reflection profiles to image subsurface geometries and field stratigraphy to measure outcrop orientations and reconstruct deformation history.

Materials Science and Engineering

In materials science and engineering, invagination principles are applied to design synthetic soft matter systems, particularly hydrogels and elastomers, to achieve controlled morphological changes that mimic biological epithelial folding for creating tunable surfaces with enhanced functionality. These structures exploit mechanical instabilities, such as buckling under compression or swelling, to form invaginated patterns that increase surface area or enable responsive behaviors. For instance, bilayer hydrogel systems composed of alginate/polyacrylamide double networks and hyaluronic acid layers can be programmed to fold into specific invagination-like geometries by differential swelling, providing adaptive interfaces for sensors or actuators.^[65] Finite element simulations play a crucial role in modeling invagination processes within soft materials, allowing engineers to predict and optimize deformation in biomechanics applications, such as tissue engineering scaffolds. These computational approaches integrate hyperelastic constitutive models to simulate buckling-induced invaginations under applied stresses, enabling the design of porous scaffolds that promote cell infiltration while maintaining structural integrity. In layered elastomer-hydrogel composites, finite element analysis reveals how interfacial adhesion and thickness ratios influence invagination onset, guiding the fabrication of scaffolds that replicate tissue folding mechanics without biological components.^[66] Invaginated architectures find practical applications in drug delivery systems and adaptive materials. For example, bowl-like multilayer polymer microcapsules can be prepared by osmotic-induced invagination of spherical precursors, which enhances cellular uptake via improved endocytosis efficiency and protects encapsulated payloads from degradation for controlled release.^[67] Biophysical parallels between biological and synthetic invagination often draw on buckling theory to quantify critical conditions for instability. In thin-film elastomers or hydrogel coatings, the onset of invagination can be modeled using the critical compressive stress for plate buckling, adapted from epithelial models:

\sigma_{cr} = \frac{\pi^2 E}{12(1 - \nu^2) (L/h)^2}

where E is the Young's modulus, \nu is Poisson's ratio, L is the span length, and h is the film thickness; this equation establishes thresholds for controlled folding in engineered systems under confinement.^[66]

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Nov 30, 2015 · We provide evidence that BMP signals are required for RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination.
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Wnt Signaling and Cell Migration - NCBI - NIH
The invagination of the cells from placodes and the formation of the five primary branches are influenced by different signals: FGF, decapentaplegic (Dpp, a ...
[25]
Fibroblast growth factor signaling in mammalian tooth development
FGF signaling regulates invagination of the dental epithelium ... The dental lamina invaginates into the mesenchyme and induces mesenchymal condensation around ...
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Christian Heinrich Pander (1794-1865) - Embryo Project Encyclopedia
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Comparative Embryology - Developmental Biology - NCBI Bookshelf
Karl Ernst von Baer extended Pander's studies of the chick embryo. He discovered the notochord, the rod of dorsalmost mesoderm that separates the embryo into ...
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[PDF] Amphibian gastrulation: history and evolution of a 125 year-old ...
The correspondence between this ori- fice and the posterior end of the embryo was briefly mentioned by von Baer (1836), following his description of early ...
[29]
Seeing Animal Ancestors in Embryos (Chapter 8)
Jul 8, 2022 · Haeckel had tied the evolutionary origin of invagination gastrulation to the emergence of a division of labor between surface ectoderm cells ...<|separator|>
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Wilhelm Roux (1850-1924) | Embryo Project Encyclopedia
Jul 22, 2009 · Wilhelm Roux was a nineteenth-century experimental embryologist who was best known for pioneering Entwickelungsmechanik, or developmental mechanics.
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https://www.jstor.org/stable/2815816
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'Not birth, marriage or death, but gastrulation': the life of a quotation ...
Jan 20, 2022 · Having coined the term 'gastrula' in 1872, Haeckel insisted that it is 'the most important and most significant embryonic form of the animal ...
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Historic Embryology Papers
Oct 25, 2020 · Historically, say pre-20th century, Embryology was not easily separated from Medicine, Anatomy and Physiology and other biological sciences.
[34]
embryology and evolution: nineteenth century hopes and twentieth
An attempt is made to assess the influence of evolution theory on the study of embry- ology by examining the assumptions held by embryologists before and ...
[35]
Induction of Embryonic Primordia by Implantation of Organizers ...
In 1924, Spemann and Mangold demonstrated that the dorsal blastopore lip of newt gastrula embryos is capable of inducing a secondary body axis when transplanted ...
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Induction into the Hall of Fame: tracing the lineage of Spemann's ...
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Interacting functions of snail, twist and huckebein during the early ...
May 1, 1994 · Two zygotic genes, snail (sna) and twist (twi), are required for mesoderm development, which begins with the formation of the ventral furrow ...
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Downregulation of basal myosin‐II is required for cell shape ...
Nov 15, 2018 · Quantitative imaging demonstrates that optogenetic activation prior to tissue bending slows down cell elongation and blocks invagination.
[39]
Optogenetic inhibition of actomyosin reveals mechanical bistability ...
Feb 23, 2022 · Combined optogenetic and computer modeling approaches reveal how mechanical bistability of the mesoderm epithelium works jointly with apical ...Missing: advances | Show results with:advances
[40]
[Invagination and evagination: a hydromechanical model] - PubMed
The model is based on the assumption that the structures demonstrating invaginations and evaginations are closed systems capable of changing their ...
[41]
Studying gastrulation by invagination: The bending of a cell sheet by ...
We used a computer model to simulate a 3D embryo with cells that can deform and adhere together to investigate the bending of a cell sheet.
[42]
Apical constriction: themes and variations on a cellular mechanism ...
May 15, 2014 · Apical constriction is a cell shape change that promotes tissue remodeling in a variety of homeostatic and developmental contexts.Missing: seminal | Show results with:seminal
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Cellular systems for epithelial invagination - Journals
Mar 27, 2017 · Apical constriction. Apical constriction is defined as a mechanism in which epithelial cells undergo apical shrinkage while keeping a more or ...
[44]
RhoA GTPase inhibition organizes contraction during epithelial ...
Aug 22, 2016 · Here, we discovered that RhoA activation is required for, but not sufficient to, promote medioapical ROCK/myosin accumulation and apical ...
[45]
Optogenetic control of apical constriction induces synthetic ... - Nature
Sep 14, 2022 · The driving force of apical constriction is actomyosin contraction ... Rho-ROCK pathway on the apical side. Because apical constriction ...
[46]
Supracellular actomyosin assemblies: master coordinators of ...
Aug 26, 2025 · (A) Schematic illustrating the apical and junction-associated position of a supracellular actomyosin cable (green) in epithelial cells.
[47]
Formation and contraction of multicellular actomyosin cables ...
Jun 1, 2020 · An emerging mechanism that appears to be important for epithelial invagination is the contraction of supracellular actomyosin cable structures ...
[48]
Supracellular actomyosin assemblies during development - PMC
Such actomyosin cables have been shown to serve several important functions, in processes such as wound healing, epithelial morphogenesis and maintenance of ...
[49]
A new mechanochemical model for apical constriction - Frontiers
The governing equations consist of an advection-diffusion-reaction system for calcium concentration which is coupled to a force balance equation for the tissue.
[50]
A simple mechanochemical model for calcium signalling in ...
We can obtain ODE (3) from the full force balance mechanical equation for a linear viscoelastic material. ... apical actin network to drive apical constriction ...
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https://pmc.ncbi.nlm.nih.gov/articles/PMC4929940/
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Acquisition of the dorsal structures in chordate amphioxus - PMC - NIH
Jun 15, 2016 · Gastrulation in amphioxus embryos starts as flattening ... During gastrulation, expression was extended within the invaginating archenteron ...
[53]
Tunicate Gastrulation - PMC - PubMed Central - NIH
Apr 23, 2020 · Endoderm invagination is the product of two distinct and sequential steps, both driven by myosin II. In the first step the apical (vegetal-most) ...
[54]
Ancestral mesodermal reorganization and evolution of the ...
Nov 9, 2015 · Gastrulation in amphioxus occurs by simple invagination with little mesodermal involution, whereas in vertebrates gastrulation is organized ...
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Invaginating Structures in Synapses – Perspective - PMC
May 24, 2021 · These invaginating structures are most elaborate in synapses mediating rapid integration of signals, such as muscle contraction, mechanoreception, and vision.
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Sensory Processing at Ribbon Synapses in the Retina and the ...
This review summarizes the current understanding of sensory processing at the ribbon synapses of the eye and the ear.
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Multiple Invagination Patterns and Synaptic Efficacy in Primate and ...
The axon terminal arborizations of type I HCs provide the HC processes into RSs in primate retinas,21,31 and those of type B HCs in rodent retinas.32 The axon ...
[58]
Synaptic ribbons foster active zone stability and illumination ... - Nature
Apr 6, 2020 · Rod photoreceptor synapses use large, ribbon-type active zones for continuous synaptic transmission during light and dark.
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Synaptic transmission at retinal ribbon synapses - PMC
The molecular organization of ribbon synapses in photoreceptors and ON bipolar cells is reviewed in relation to the process of neurotransmitter release.
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Dynamics of vacuoles and actin filaments in guard cells and their ...
Jul 9, 2009 · ... guard cells of closed stomata might be a result of tonoplast invagination accompanied by a decrease in vacuolar volume, and the expansion of ...
[61]
Excretion and folding of plasmalemma function to accommodate ...
Jul 5, 2010 · Guard cells control stomatal movement thereby regulating gas exchange in plants. ... invagination, and this type of structure could also be found ...
[62]
Cargo regulates clathrin-coated pit invagination via clathrin light ...
Sep 18, 2018 · Clathrin-mediated endocytosis (CME) is a major pathway that controls receptor uptake from the plasma membrane and is essential for physiological ...
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Epithelial invagination by a vertical telescoping cell movement in ...
May 12, 2020 · 1a–c). In this mechanism, canopy contraction, basal layer cells become wedge-shaped due to the extrinsic contraction of the overlying canopy.
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Recumbent folds: Key structural elements in orogenic belts
Recumbent folds are key structures in the development of orogenic belts. They occur in a variety of geological settings and have different sizes and geometry.
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Analogue modelling of basin inversion: a review and future ... - SE
Dec 16, 2022 · Basin inversion involves the reversal of subsidence in a basin due to compressional tectonic forces, leading to uplift of the basin's ...
[66]
Fold-and-thrust belts and associated basins: a perspective on their ...
Nov 16, 2022 · Fold-thrust belts are structural features that accommodate upper-crustal shortening by the growth of a series of thrusts and folds (Chapple 1978 ...
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Formation of recumbent folds during synorogenic crustal extension ...
Jun 2, 2017 · The folds developed with axes oblique to parallel to the direction of bulk stretching. I suggest that folding of initially nonhorizontal layers ...
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Basement Controls on Structural Evolution in Thin‐Skinned Thrust ...
Jan 22, 2025 · Interpretations of high-resolution 3D seismic reflection imagery from NE Jura fold- thrust belt are presented with structural restorations.
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Programmable tissue folding patterns in structured hydrogels - PMC
Here, we describe a bilayer hydrogel folding system composed of alginate/polyacrylamide double network (DN) and hyaluronic acid (HA) hydrogels to generate ...
[70]
[PDF] Mechanical Instabilities of Soft Materials: Creases, Wrinkles, Folds ...
This thesis explores different types of mechanical instabilities: creases, wrinkles, folds, and ridges. We start with studying creases in different materials.
[71]
https://doi.org/10.1103/PhysRevLett.134.118402