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Cell polarity

Cell polarity refers to the asymmetric organization of proteins, lipids, and organelles within a cell, resulting in the formation of distinct functional domains in the plasma membrane and cytoplasm that enable specialized cellular processes such as directed migration, vectorial transport, and asymmetric division.^[1] This nonuniform distribution arises from the unequal localization of a limited set of regulatory molecules, which propagate asymmetry across the cell to influence broader structural and functional outcomes.^[2] In essence, cell polarity transforms a symmetric cellular state into one with defined axes, essential for both unicellular organisms like yeast and multicellular tissues.^[3] The establishment of cell polarity typically involves a combination of intrinsic and extrinsic cues that initiate symmetry breaking, followed by reinforcement through cytoskeletal rearrangements and targeted protein trafficking.^[1] Key regulators include Rho GTPases such as Cdc42, which activate downstream effectors to cluster at specific sites and drive actin polymerization, often via positive feedback loops that amplify local signals while global inhibitors prevent ectopic polarization.^[3] In epithelial cells, conserved protein modules like the PAR complex (involving PAR-3, PAR-6, and aPKC) and the Scribble (Scrib) module (comprising Scrib, Dlg, and Lgl) antagonize each other to define apical-basal domains, with the Scrib module exhibiting a hierarchical localization dependency that restricts PAR activity to the apical region.^[4] These mechanisms are highly conserved across species, from plants where DIX domain polymerization assembles polarity complexes to animals where they coordinate tissue-level organization.^[5] Cell polarity is fundamental to multicellular development, underpinning epithelial barrier integrity, immune cell activation, and embryonic patterning, with disruptions linked to diseases including cancer and developmental disorders.^[1] For instance, in response to external signals like cell-cell adhesion or fertilization, polarity directs cytokine secretion in T cells or axis formation in embryos such as Caenorhabditis elegans.^[2] Even in the absence of cues, cells like neutrophils or yeast buds can spontaneously polarize through self-organizing networks involving phosphoinositides and GTPases, highlighting the robustness of these systems.^[3] Overall, polarity ensures coordinated cellular behavior, from single-cell motility to complex tissue morphogenesis.^[4]

Overview

Definition

Cell polarity is defined as the asymmetric distribution of cellular components, including proteins, lipids, organelles, and elements of the cytoskeleton, along a specific axis within the cell, which enables functional specialization and directed cellular processes. This asymmetry breaks the inherent symmetry of the cell, creating spatially restricted domains that coordinate essential functions such as directed migration, asymmetric division, and tissue formation.^[1] In essence, cell polarity transforms a uniform cellular structure into one with defined "front" and "rear" or "top" and "bottom" regions, allowing the cell to respond anisotropically to environmental cues.^[6] The phenomenon was first observed through early microscopy studies of eggs and embryos in the late 19th century, where researchers noted visible asymmetries in cytoplasmic organization, such as the animal-vegetal axis in sea urchin and ascidian eggs.^[7] Theodor Boveri's detailed examinations of sea urchin embryos using serial sectioning techniques revealed polarized centrosome positioning and cleavage patterns, laying foundational insights into embryonic asymmetry.^[7] Modern molecular understanding of cell polarity was advanced in the 1980s through genetic screens in the model organism Caenorhabditis elegans, which identified maternal-effect genes essential for establishing cytoplasmic asymmetry in the one-cell embryo.^[8] A key principle of cell polarity is the formation of distinct membrane domains, such as apical and basal surfaces in epithelial cells, which dictate behaviors like adhesion, transport, and motility.^[1] These domains arise from localized enrichment or exclusion of molecular components, ensuring that cellular activities are compartmentalized and oriented along the polarity axis.^[1]

Types of Cell Polarity

Cell polarity manifests in several distinct forms, primarily classified by the axis of asymmetry and the context of its establishment. The two major types observed in multicellular organisms are apical-basal polarity and planar cell polarity (PCP), which differ in their orientation relative to the tissue plane and their roles in tissue organization.^[9] Additionally, polarity can be categorized as intrinsic or extrinsic based on whether it arises from cell-autonomous mechanisms or environmental cues, a distinction that applies across various cell types including unicellular organisms.^[1] Apical-basal polarity establishes asymmetry along the axis perpendicular to the epithelial tissue plane, dividing the cell into distinct domains: the apical domain facing the lumen or external environment, the lateral domain involved in cell-cell adhesions, and the basal domain anchored to the basement membrane. This type is essential for epithelial barrier function and tissue architecture in structures like sheets or tubes.^[10] For instance, in Drosophila embryonic epithelia, apical-basal polarity organizes membrane domains during cellularization.^[10] Planar cell polarity (PCP), in contrast, refers to coordinated asymmetry within the plane of the epithelium, orthogonal to apical-basal polarity, which aligns cellular structures across a tissue to guide collective behaviors such as oriented divisions or migrations. PCP ensures uniform orientation of features like actin-based protrusions, enabling tissue-wide patterning. Examples include the distal pointing of hairs on Drosophila wings and the posterior alignment of mammalian hair follicles.^[10] Beyond these epithelial forms, other types of polarity occur in non-epithelial contexts, such as intrinsic polarity in unicellular organisms, where cells autonomously select sites for growth or division without external input; for example, budding yeast (Saccharomyces cerevisiae) establishes polarity at axial or bipolar sites via internal cytoskeletal cues like septins.^[1] Extrinsic polarity, conversely, is induced by environmental signals, such as substrate adhesion or chemical gradients, which dictate the axis in cells like migrating neurons or responding yeast cells.^[1] The key distinction lies in establishment: intrinsic polarity is cell-autonomous and often inherited from prior divisions, while extrinsic polarity depends on external interactions to break symmetry.^[10]

Mechanisms of Polarity

Establishment

Cell polarity establishment begins with symmetry breaking, a process where cells select a specific axis to organize their internal components despite initial uniformity. This symmetry breaking is often triggered by initial cues, such as localized activation of signaling proteins, mechanical forces from the cytoskeleton, or extracellular signals like Wnt gradients that provide directional information.30586-X) For instance, Wnt signaling acts as a primordial symmetry-breaking cue in multicellular development by creating short-range gradients that bias polarity axis selection.30586-X) Mechanical forces, including actomyosin contractility, can also initiate asymmetry by generating cortical flows that redistribute polarity determinants.00144-4) The establishment phase typically involves transient polarization, where weak initial asymmetries are amplified, followed by stabilization of the polarity axis. In the Caenorhabditis elegans zygote, sperm entry serves as the primary cue, introducing the centrosome that nucleates microtubules and triggers posterior contractility, thereby defining the anterior-posterior axis.00790-9) This cue induces a rapid redistribution of polarity proteins, leading to a polarized cortical domain within minutes.00525-9) Amplification of these initial asymmetries relies on diffusion barriers that restrict protein mobility in the membrane and positive feedback loops that reinforce localized accumulation. Diffusion barriers, such as those formed at membrane boundaries, compartmentalize the cortex to prevent mixing of polarity factors, thereby sustaining nascent domains.01350-5) Positive feedback loops, often involving GTPase activation, further enhance this by recruiting more effectors to the site of initial activation, creating stable clusters from subtle cues.^[11] Conserved proteins like Cdc42 contribute to this process through such feedback mechanisms.01295-5) Mathematically, spontaneous symmetry breaking in cell polarity can be modeled using reaction-diffusion systems, where activator-inhibitor dynamics lead to Turing patterns that generate stable spatial domains. In these models, a short-range activator (e.g., promoting local accumulation) diffuses slower than a long-range inhibitor (e.g., suppressing activity elsewhere), resulting in patterned polarity from uniform starting conditions.70444-2) This framework explains how cells achieve robust axis selection without external biases in certain contexts.00201-2)

Maintenance

Once cell polarity is established, its maintenance relies on continuous recycling of polarized components through vesicular trafficking pathways, which counteract the tendency for proteins and lipids to diffuse randomly across the plasma membrane. In eukaryotic cells, endocytic internalization followed by targeted recycling delivers polarity determinants, such as PIN proteins in plants, back to specific domains, ensuring their asymmetric localization over time.^[12] Cytoskeletal dynamics, particularly actin cables and microtubules, guide these vesicles to polar sites, preventing dilution by diffusion; for instance, actin-mediated transport in budding yeast sustains Cdc42p clusters at the bud tip.^[1] This recycling is constitutive, with recovery times for polar proteins like PIN1-GFP occurring within minutes after perturbation, highlighting the efficiency of these mechanisms in steady-state polarity.^[12] In multicellular contexts, such as epithelial tissues, cell-cell junctions play a critical role in sustaining polarity by forming diffusion barriers that segregate membrane domains. Tight junctions, composed of claudins and occludins, create a "fence" that restricts the lateral movement of lipids and proteins between apical and basolateral surfaces, thereby preserving apico-basal asymmetry.^[13] This barrier function is essential for domain separation, as disruption of tight junctions, such as through ZO-1 knockdown, leads to mixing of apical and basolateral markers like gp135 and E-cadherin.^[13] In addition to their structural role, these junctions integrate with the cytoskeleton via adaptor proteins like ZO-1, reinforcing stability against mechanical perturbations. Feedback loops further ensure the persistence of polarity by amplifying correct domains while suppressing ectopic ones. Positive feedback, often involving Rho GTPases like Cdc42, reinforces polar clusters through actin assembly and vesicle targeting, as seen in yeast where Cdc24-mediated activation sustains bud site growth.^[1] Negative feedback mechanisms, such as those mediated by actomyosin contractility, inhibit off-site polarization; for example, myosin II-driven tension at cell edges in epithelial cells limits Cdc42 activity elsewhere, maintaining a single axis.30775-3) Counteracting loops, including Bem1-Cdc24 positive reinforcement balanced by Rdi1-mediated GDI dissociation, equalize and stabilize polarity sites, preventing multifocal asymmetry.^[14] Polarity also adapts dynamically to environmental cues like mechanical stress and nutrient gradients, involving remodeling to preserve function. Under mechanical stress, such as tensile forces in tissues, integrins and YAP/TAZ pathways trigger cytoskeletal reorganization, aligning polarity axes in endothelial cells via actomyosin flows that enhance barrier integrity.^[15] In response to nutrient gradients, budding yeast remodel polarity toward high-glucose sites via Cdc42 signaling, sustaining directed growth.^[16] During cell division, polarity undergoes transient remodeling to ensure inheritance; in asymmetric divisions, cortical actomyosin flows redistribute polarity proteins like PAR complexes, maintaining daughter cell asymmetry through cytokinesis.^[17] This adaptability links maintenance to broader cellular processes, allowing polarity to respond without complete re-establishment.

Molecular Components

Conserved Proteins and Pathways

Cell polarity is orchestrated by several evolutionarily conserved protein complexes and signaling pathways that establish and maintain asymmetric distributions of cellular components. Central to this process is the Partitioning defective (PAR) pathway, first identified in Caenorhabditis elegans embryos, where it regulates the segregation of cytoplasmic determinants during asymmetric cell division.^[18] The core PAR proteins include PAR-1, a serine/threonine kinase that localizes to the posterior cortex; PAR-2, a RING domain protein that promotes posterior identity; and the anterior complex comprising PAR-3, a scaffold protein, PAR-6, a PDZ-domain adaptor, and atypical protein kinase C (aPKC).^[8] These proteins form mutually exclusive cortical domains through reciprocal phosphorylation: aPKC phosphorylates PAR-1 and PAR-2 to exclude them from the anterior, while PAR-1 inhibits aPKC activity in the posterior, thereby stabilizing polarity via a dynamic feedback loop.^[19] Rho family GTPases, particularly Cdc42 and Rac1, act as molecular switches to link polarity cues to cytoskeletal reorganization. Cdc42, activated by guanine nucleotide exchange factors (GEFs) such as Cdc24 in yeast or its mammalian homologs, recruits downstream effectors like the Wiskott-Aldrich syndrome protein (WASP) family and WAVE complex to promote Arp2/3-mediated actin polymerization at leading edges or budding sites.^[20] Similarly, Rac1 drives lamellipodia formation in migrating cells by activating the WAVE complex, ensuring directed protrusion and adhesion at polarity fronts.^[21] These GTPases cycle between GTP-bound (active) and GDP-bound (inactive) states, with GTPase-activating proteins (GAPs) providing spatial restriction to amplify local signals.^[20] The planar cell polarity (PCP) core module coordinates tissue-wide orientation through non-canonical Wnt signaling, independent of β-catenin. Key components include the transmembrane receptor Frizzled, which interacts with the cytoplasmic scaffold Dishevelled to recruit the multipass protein Flamingo (Celsr in vertebrates) and the effector Van Gogh (Vangl in vertebrates) on neighboring cells.^[22] This asymmetric complex distribution—Frizzled/Dishevelled on one side and Van Gogh/Prickle on the opposite—propagates polarity via intercellular interactions, often involving cytoskeletal regulators like Rho GTPases for planar alignment in epithelia.^[23] These pathways exhibit profound evolutionary conservation, tracing back to unicellular organisms. In budding yeast (Saccharomyces cerevisiae), homologs such as Bem1 (a scaffold akin to PAR-3/PAR-6) and the Kin1/Kin2 kinases (PAR-1 orthologs) cooperate with Cdc42 to establish bud site polarity, mirroring metazoan mechanisms.^[24] PCP-like modules, including Frizzled and Dishevelled homologs, appear in choanoflagellates, the closest unicellular relatives to animals, underscoring an ancient origin for coordinated polarity from single-celled ancestors to complex multicellular tissues.^[25]

Regulatory Interactions

Cell polarity pathways integrate with cell cycle regulators to ensure polarity is coordinated with division. For instance, cyclin-dependent kinase 1 (CDK1) phosphorylates PAR-3 at a conserved serine residue (S180 in Drosophila Bazooka), weakening its apical localization and promoting mitotic progression without disrupting overall polarity in neuroblasts.^[26] This inhibition prevents premature polarity re-establishment during mitosis, linking polarity dynamics to CDK1 activity peaks.^[26] Similarly, adhesion molecules like E-cadherin stabilize lateral membrane domains by forming dynamic complexes with ankyrin-G, which restrict mobility and maintain epithelial polarity through junctional reinforcement.^[27] Feedback loops within the PAR-aPKC system generate bistable states essential for stable polarity. Phosphorylation-dephosphorylation cycles drive mutual antagonism: atypical protein kinase C (aPKC) phosphorylates PAR-3, promoting its exclusion from posterior domains, while protein phosphatase 1 (PP1) counteracts this by dephosphorylating PAR-2 and other targets, allowing anterior-posterior segregation.^[19] These cycles, combined with positive feedbacks like PAR-3 oligomerization and Cdc42 activation of PAR-6/aPKC, create ultrasensitive responses that lock cells into polarized states.^[19] Mathematical models capture this bistability through reaction-diffusion equations, such as a simplified representation for anterior PAR proteins (e.g., PAR-3 dynamics influenced by Cdc42 and posterior factors proxying aPKC activity):

\frac{d[\text{PAR-3}]}{dt} = k_1 [\text{Cdc42}] ([\text{PAR-3}]_{\text{total}} - [\text{PAR-3}]) - k_2 [\text{aPKC}] [\text{PAR-3}]

where k_1 and k_2 are rate constants, enabling multiple steady states that stabilize distinct domains.^[28] At the tissue level, single-cell polarity aligns through junctional transmission in planar cell polarity (PCP), mediated by the Fat/Dachsous (Fat/Ds) pathway. Fat and Dachsous cadherins form heterophilic bonds that propagate asymmetry across cells via graded Ds expression and Four-jointed kinase modulation, coordinating PCP with core Frizzled-Dishevelled signals at junctions.^[23] This intercellular relay ensures collective tissue orientation without global cues.^[29] Recent advances highlight liquid-liquid phase separation (LLPS) in concentrating polarity factors post-2020. In Drosophila neuroblasts, the PAR complex undergoes cell cycle-dependent LLPS, forming condensates that enhance aPKC activity and apical clustering, driven by multivalent interactions in PAR-3 and Bazooka.^[30] This mechanism provides a biophysical basis for rapid polarity amplification, integrating with existing networks for robust domain formation.30462-7)

Examples in Organisms

Unicellular Organisms

In unicellular organisms, cell polarity manifests as asymmetric organization of cellular components to direct growth, division, or movement, often in response to intrinsic cues or environmental signals. In the budding yeast Saccharomyces cerevisiae, polarity is established at predetermined cortical sites for bud emergence, enabling polarized growth. The Ras-family GTPase Rsr1 (also known as Bud1) and its regulators play a central role in selecting these sites by linking spatial landmarks, such as bud scars or axial proteins like Bud8 and Bud9, to the activation of the Rho GTPase Cdc42.^[31] Rsr1 interacts directly with Cdc42 and its guanine nucleotide exchange factor (GEF) Cdc24, recruiting them to the landmark to initiate polarity.^[32] Cdc42 then clusters at the site through positive feedback involving Bem1 and PAK kinases, directing actin cable polymerization and vesicular transport to sustain growth at the bud tip.^[33] In other unicellular models like amoebae and fission yeast, polarity is often driven by external cues such as chemotactic gradients, contrasting with the landmark-based system in budding yeast. In the social amoeba Dictyostelium discoideum, chemotaxis toward cyclic AMP (cAMP) gradients establishes polarity by activating phosphoinositide 3-kinase (PI3K) at the leading edge, producing phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to recruit actin regulators and promote pseudopod protrusion.^[34] This PI3K signaling suppresses lateral pseudopods while enhancing front-directed actin assembly, ensuring persistent migration.^[35] Similarly, in fission yeast Schizosaccharomyces pombe, chemotactic responses during mating reorient polarity toward pheromone sources; cells form directed projections (shmoos) via Cdc42 activation by GEFs like Scd1 and Scd2, which integrate gradient sensing with cytoskeletal reorganization at the plasma membrane.^[36] In both cases, Rho GTPases like Cdc42 coordinate leading-edge protrusion analogous to pseudopod formation in amoebae.^[33] Cell polarity in unicellular organisms represents an ancestral trait, with Rho GTPases such as Cdc42 and Rac predating multicellularity and enabling essential processes like mating and asymmetric division. Phylogenetic analyses trace Rho family origins to a common Rac-like ancestor in early eukaryotes, with Cdc42 and Rho subfamilies diverging over 1.5 billion years ago in unicellular lineages including fungi and protists.^[37] These GTPases regulate actin dynamics for polarity in unicellular contexts, providing a conserved module later adapted for tissue organization.^[38] Unicellular organisms serve as powerful experimental models for polarity, where genetic perturbations reveal the consequences of disrupted mechanisms. In S. cerevisiae, mutations in Rsr1 or Cdc42 regulators like Cdc24 lead to random bud site selection and isotropic growth, resulting in multibudded or spherical cells unable to focus secretion.^[33] Similarly, in S. pombe, deletion of GEFs such as Scd1 causes loss of tip-focused growth, yielding round cells with delocalized Cdc42 activity and uniform expansion.^[33] These defects underscore the precision of polarity circuits, as even partial inactivation of GAPs like Rga1 or Rga4 shifts growth from axial to isotropic patterns.^[39]

Animal Cells

In animal tissues, epithelial cells exhibit apical-basal polarity, where the apical domain faces the external environment or lumen and features specialized structures like microvilli that increase surface area for absorption and secretion, while the basolateral domain anchors to the extracellular matrix via integrins to maintain tissue architecture.^[40] This polarity is crucial for barrier function, as tight junctions separate the apical and basolateral domains, preventing paracellular leakage and enabling vectorial transport across epithelia, such as in the intestinal lining where it supports nutrient uptake and pathogen defense.^[40] Disruptions in this organization, such as mislocalized integrins, compromise adhesion and lead to loss of tissue integrity.^[41] Neurons display axon-dendrite polarity, essential for directional signal propagation in neural circuits, where one neurite elongates into a long axon while others form branched dendrites.^[42] This asymmetry arises during initial neurite outgrowth, guided by intrinsic cues like the Par3/Par6/aPKC complex and extrinsic signals such as laminin substrates, which specify the future axon.^[42] Microtubule-associated protein 2 (MAP2) enriches in dendrites to stabilize microtubules and promote branching, whereas Tau predominates in axons to support their elongation and transport functions.^[42] In hippocampal neurons, for instance, MAP2 deficiency reduces dendritic length and microtubule density, underscoring its role in polarity maintenance.^[42] Migratory cells, such as fibroblasts and immune cells, establish front-rear polarity to enable directed movement through tissues during processes like wound repair and immune surveillance.^[43] At the leading edge, lamellipodia protrude via Rac1 activation of the WAVE complex and Arp2/3-mediated actin branching, driving membrane extension and adhesion in fibroblasts and neutrophils.^[43] In contrast, myosin II accumulates at the cell rear, generating contractile forces that retract the trailing edge and propel forward motion, as seen in dendritic cells where rear-localized myosin IIA forms a gradient essential for maximal migration speed in 3D environments.^[44] This bipolar organization ensures efficient chemotaxis, with Rac1 knockout in fibroblasts eliminating lamellipodia and impairing matrix invasion.^[43] Recent studies highlight the role of planar cell polarity (PCP) pathways in coordinating collective migration of animal cell sheets during wound healing, where mechanical cues polarize protein complexes like ADIP-Diversin to align cell movements and close gaps efficiently.^[45] In vertebrate models, PCP signaling integrates tissue tension to orient protrusions across groups of epithelial cells, promoting synchronized repair without disrupting overall tissue architecture, as demonstrated in embryonic wound assays in 2025.^[45] This intercellular coordination contrasts with single-cell polarity but relies on conserved coregulators like those in the PAR complex for local asymmetry.^[45]

Plant Cells

In plant cells, apical-basal polarity is prominently established and maintained through the polar localization of PIN-FORMED (PIN) auxin efflux carriers, which generate directional auxin gradients essential for processes like gravitropism in roots and stems.^[46] These transporters, such as PIN3, relocalize to the lower plasma membrane in response to gravity, facilitating auxin flow toward the root tip and promoting differential cell elongation on the upper and lower sides.^[47] This polarity is crucial for root skewing and bending, as mutants lacking functional PIN proteins exhibit defective gravitropic responses.^[48] Unlike animal cells, plant cell polarity is constrained by rigid cell walls, which fix the orientation of cellular expansions once established, with cellulose microfibrils deposited by cellulose synthase complexes (CSCs) guiding anisotropic growth.^[49] Cortical microtubules (CMTs) play a pivotal role by aligning CSCs at the plasma membrane, ensuring that newly synthesized cellulose fibers follow the microtubule orientation to reinforce cell wall anisotropy and maintain polarity during diffuse growth.^[50] This microtubule-CSC interaction is dynamically regulated, as disruptions in CMT arrays lead to misoriented cellulose deposition and loss of cell shape polarity.^[51] Intercellular polarity in plants is exemplified in the stomatal lineage, where asymmetric cell divisions produce guard mother cells that differentiate into polar guard cells surrounding stomatal pores. The protein BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) establishes this polarity by localizing asymmetrically in precursor cells, directing the division plane and enforcing distinct daughter cell fates through MAPK signaling feedback loops.^[52] BASL's cortical polarization persists across divisions, ensuring oriented expansion and proper stomatal patterning on leaf surfaces.^[53] Recent advances highlight the interplay between the cytoskeleton and polarity regulators in diffuse growth, particularly through ROP GTPases, which are plant-specific homologs of animal Rho GTPases and orchestrate microtubule array organization to direct cell expansion.^[54] In 2025 research, ROP signaling was shown to promote microtubule-mediated anisotropic growth while integrating with actin dynamics for localized tip growth, underscoring its conserved role in polarity establishment across plant tissues.^[55] These findings reveal how ROPs fine-tune cortical microtubule bundling to sustain polarity under mechanical stresses during diffuse cell elongation.^[56]

Biological Significance

Role in Development

Cell polarity plays a pivotal role in embryonic development by directing axis formation and tissue patterning across diverse organisms. In vertebrates, during gastrulation, planar cell polarity (PCP) signaling coordinates convergent extension movements essential for neural tube closure, where polarized cell rearrangements narrow and elongate the neural plate to form the midline structure.^[57] PCP components, such as Frizzled and Dishevelled, asymmetrically localize to drive these morphogenetic changes, ensuring proper apposition of neural folds.^[58] Additionally, cell polarity aligns motile cilia in the node, generating leftward fluid flow that breaks bilateral symmetry and establishes left-right asymmetry in organ positioning.^[59] This ciliary orientation, regulated by PCP pathways, directs asymmetric gene expression, such as Nodal on the left side, to specify visceral situs.^[60] In invertebrate models like Drosophila melanogaster, cell polarity in the oocyte establishes the anterior-posterior axis through localized signaling. The oocyte nucleus repositions dorsally, leading to posterior accumulation of Gurken protein, which activates the EGFR receptor in overlying follicle cells to induce posterior fate and repress anterior determinants.^[61] This Gurken-EGFR interaction polarizes the eggshell and microtubule cytoskeleton, directing localization of anterior (Bicoid) and posterior (Oskar) mRNAs for embryonic patterning.^[62] A subsequent dorsal shift of Gurken refines dorsoventral polarity, ensuring coordinated axis formation.^[63] In plants, cell polarity mediated by polar auxin transport governs developmental patterning, particularly through the PIN-FORMED (PIN) efflux carriers that create auxin maxima. Polar localization of PIN1 directs auxin flow toward convergence points in leaf primordia, regulating phyllotaxy by positioning new organs at inhibitory minima.^[64] In vascular development, this polarity establishes vein patterns, with auxin canalization reinforcing continuous files of polarized cells to form procambial strands.^[65] These mechanisms highlight the conservation of cell polarity in axis formation across kingdoms, from ciliary and PCP-driven processes in animals to auxin-directed flows in plants, where disruptions in polarity components lead to teratogenic defects such as randomized organ situs or malformed axes.^[66] This evolutionary preservation underscores polarity's fundamental role in coordinating multicellular morphogenesis.^[17]

Implications in Disease

Disruption of apical-basal polarity is a hallmark of epithelial-mesenchymal transition (EMT) in cancer, where epithelial cells lose their polarized architecture and cell-cell adhesions, gaining migratory and invasive properties that facilitate metastasis.^[67] Transcription factors such as Snail and Twist drive this process by repressing E-cadherin expression, a key component of adherens junctions that maintains epithelial polarity; this repression leads to reduced cell adhesion and increased tumor cell motility.^[67] In breast cancer, for instance, Twist overexpression correlates with E-cadherin loss and is associated with invasive lobular carcinomas, promoting intravasation into blood vessels and distant metastasis.^[67] Recent studies have shown that disrupted cell polarity in breast cancer cells promotes an immunosuppressive tumor microenvironment, impairing immune cell function and facilitating tumor progression.^[68] Mutations in planar cell polarity (PCP) pathway genes, such as VANGL1, contribute to neurodevelopmental disorders including neural tube defects (NTDs) like spina bifida.^[69] Heterozygous VANGL1 variants disrupt PCP signaling, impairing convergent extension movements essential for neural tube closure during embryogenesis, with studies identifying such mutations in patients with spina bifida and associated vertebral malformations.^[70] Similarly, VANGL2 mutations exacerbate NTD severity in compound heterozygous models, linking PCP defects to open spina bifida and craniorachischisis.^[69] Polarity imbalances also underlie other pathologies, such as polycystic kidney disease (PKD), where ciliary dysfunction disrupts oriented cell division and planar cell polarity in renal epithelia.^[71] In autosomal dominant PKD, mutations in PKD1 or PKD2 impair polycystin function in primary cilia, leading to aberrant Wnt signaling that misorients mitotic spindles and promotes cyst formation through loss of tubular polarity.^[71] Recent studies have further connected dysregulation of PAR complex proteins such as aPKC, which contribute to neuronal polarity, to Alzheimer's disease pathology, including associations with neurofibrillary tangles and potential contributions to neuronal degeneration.^[72]^[73] Therapeutic strategies targeting polarity regulators show promise for restoring balance in disease states, particularly in cancer.^[74] Inhibitors of Rho GTPases, such as ROCK (for RhoA/C) and MRCK (for Cdc42), disrupt actin-mediated contractility and invadopodia formation, reducing tumor cell migration and invasion in preclinical models of pancreatic and skin cancers.^[74] Similarly, targeting PAR pathways or their effectors like aPKCs could reinstate epithelial polarity to counteract EMT, with ongoing efforts exploring Cdc42 inhibitors to block polarity-driven metastasis.^[74]

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