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Prophase

Prophase is the first stage of mitosis and the initial phase of meiosis in the eukaryotic cell cycle, during which replicated chromosomes condense into compact, visible structures to facilitate their subsequent segregation, and the cellular machinery begins to reorganize for division.^[1] In this phase, chromatin fibers, which were diffuse during interphase, coil and shorten to form distinct chromosomes, each consisting of two identical sister chromatids joined at the centromere by cohesin proteins, becoming resolvable under a light microscope.^[2] In mitotic prophase, the duplicated centrosomes—organelles that serve as microtubule-organizing centers—separate and migrate to opposite poles of the nucleus, propelled by elongating microtubules, while the mitotic spindle apparatus begins to assemble from these poles, and the nucleolus typically disassembles as the nuclear envelope remains intact until the transition to prometaphase.^[1] This stage prepares the cell for the alignment and separation of chromosomes in subsequent mitotic phases, ensuring accurate distribution of genetic material to daughter cells during somatic cell division.^[2] Although brief in most cells, prophase sets the foundation for the symmetric division characteristic of mitosis, which maintains the chromosome number.^[1] Prophase also occurs in meiosis, but with significant variations, particularly in prophase I of meiosis I, which is prolonged and divided into five substages—leptotene, zygotene, pachytene, diplotene, and diakinesis—collectively occupying up to 90% of the meiotic process in some organisms.^[3] During meiotic prophase I, homologous chromosomes pair (synapsis) via the formation of the synaptonemal complex, enabling genetic recombination through crossovers between nonsister chromatids, which generate chiasmata that physically link homologs and promote genetic diversity in gametes.^[3] In contrast, prophase II of meiosis II resembles mitotic prophase, lacking homologous pairing but involving chromosome condensation and spindle initiation to separate sister chromatids.^[3] These events underscore prophase's critical role in both proliferative and reductive divisions essential for growth, repair, and reproduction.^[2]

General Concepts

Definition and Role in Cell Division

Prophase is the initial stage of the M phase in the eukaryotic cell cycle, marking the entry into cell division through the condensation of chromatin into visible chromosomes and the early assembly of the mitotic spindle apparatus.^[4] This phase occurs in both mitosis, which divides somatic cells to produce genetically identical daughters, and meiosis, which generates gametes for sexual reproduction.^[5] In prophase, the chromosomes become compact structures capable of independent movement, while centrosomes begin to separate, laying the groundwork for spindle formation that will facilitate chromosome segregation.^[4] In mitosis, prophase plays a critical role in ensuring precise chromosome alignment and equitable separation to two daughter cells, thereby maintaining genomic stability and preventing conditions like aneuploidy that arise from unequal chromosome distribution.^[4] The condensation and initial spindle setup during this phase allow for the subsequent attachment of microtubules to kinetochores, enabling the bipolar forces needed for accurate partitioning of the replicated genome. Without these preparatory events, errors in segregation could lead to cellular dysfunction or disease.^[4] In meiosis, prophase—particularly its extended form in prophase I—facilitates genetic recombination through homologous chromosome pairing and crossing over, introducing diversity while setting the stage for reductional division that halves the chromosome number to produce haploid gametes.^[6] This process ensures that gametes carry a single set of chromosomes, essential for restoring diploidy upon fertilization and promoting evolutionary variation.^[5] The stage was first described in 1879 by German biologist Walther Flemming, who observed the thread-like condensation of chromatin in epithelial cells of salamander larvae using aniline dyes, coining the term "mitosis" for the thread-forming process.^[7] Prophase ends with the nuclear envelope still intact, transitioning into prometaphase where the nuclear envelope breaks down and chromosomes can interact freely with the spindle.^[8]

Key Events and Stages

Prophase represents the initial phase of mitosis and meiosis, characterized by a series of conserved cellular reorganizations that prepare the cell for chromosome segregation. Universally across eukaryotic cell division, the process begins with the progressive coiling and shortening of chromosomes, driven by the action of condensin complexes that compact chromatin into discrete, visible structures. This condensation is essential for efficient chromosome handling during later stages. In animal cells, centrosomes, which duplicated earlier in the cell cycle, separate and migrate toward opposite poles of the nucleus, establishing the bipolar axis for spindle formation. Concurrently, these centrosomes nucleate microtubules, initiating the assembly of the mitotic spindle apparatus that will facilitate chromosome alignment and separation. Additionally, the nucleolus undergoes partial disassembly during prophase, with the dispersal of ribosomal components and the loss of nucleolar integrity, allowing access to chromosomal regions and preventing interference with spindle dynamics. In mitosis, prophase proceeds as a single, continuous phase without distinct substages, culminating in the breakdown of the nuclear envelope to transition into prometaphase. In contrast, meiotic prophase I is markedly extended and subdivided into five sequential substages—leptotene, zygotene, pachytene, diplotene, and diakinesis—each marked by specific events such as chromosome pairing and recombination. Prophase II of meiosis, occurring after the first meiotic division, is brief and structurally analogous to mitotic prophase, lacking the extended recombination processes of prophase I. The temporal dynamics of prophase vary significantly between mitotic and meiotic contexts. In mammalian somatic cells, mitotic prophase typically lasts 10-20 minutes, representing a rapid preparatory interval within the overall 30-60 minute mitotic duration. Meiotic prophase I, however, can extend dramatically, lasting months in murine oocytes or up to several decades in human oocytes arrested at the diplotene stage, reflecting adaptations for gamete maturation and storage. These prophase events exhibit remarkable evolutionary conservation across eukaryotes, from unicellular yeasts to multicellular humans, underscoring their ancient origins in the last eukaryotic common ancestor. Core mechanisms, including chromosome condensation via condensins and centrosomal microtubule nucleation, are preserved in diverse lineages, highlighting their fundamental role in ensuring accurate genome transmission despite variations in cell type and division mode.

Observation and Visualization

Staining Techniques

Classical staining techniques, such as hematoxylin and eosin (H&E), are widely used to visualize prophase in histological sections of dividing cells. In H&E preparations, hematoxylin binds to the acidic DNA in condensing chromatin, rendering prophase chromosomes as prominent dark-purple threads against a lighter cytoplasmic background stained pink by eosin.^[9] This method highlights the transition from diffuse interphase chromatin to the more compact structures of early prophase.^[10] The Feulgen stain offers DNA-specific visualization of prophase chromosomes by hydrolyzing DNA to expose aldehyde groups, which then react with Schiff's reagent to produce magenta-colored threads. This technique is particularly effective for quantifying DNA content and observing the progressive condensation of chromatin into visible threads during prophase in both mitotic and meiotic cells.^[11] In plant tissues, Feulgen staining has been applied to confocal microscopy to delineate prophase chromosomes with high resolution.^[12] Fluorescent dyes like 4',6-diamidino-2-phenylindole (DAPI) and Hoechst 33342 provide selective binding to the minor groove of A/T-rich DNA regions, enabling the detection of chromosome condensation under UV light excitation. During prophase, these dyes reveal bright blue fluorescence in condensing chromatin, allowing real-time tracking of structural changes from diffuse to thread-like forms.^[13] DAPI, in particular, has been used to study early prophase condensation in mammalian cells, where it highlights the folding of chromatin fibers into linear structures.^[14] For cytogenetic analysis of meiotic prophase, aceto-orcein staining in squashed preparations accentuates chromosome morphology by dyeing nucleic acids purple-red, facilitating detailed examination of stages like leptotene and zygotene. This method, involving acetic acid and orcein, preserves chromosome integrity while enhancing contrast for synaptonemal complex visualization. These staining approaches differentiate prophase from interphase by exploiting the increased chromatin density, which results in more intense staining and distinct thread-like patterns. For example, Giemsa banding, primarily for metaphase karyotyping, can be adapted to late prophase chromosomes to reveal preliminary band resolutions, with late prophase showing 2-3 times more bands than mid-metaphase due to partial condensation.^[15]

Microscopy Methods

Light microscopy techniques, such as phase-contrast and differential interference contrast (DIC), enable the observation of prophase dynamics in living cells without the need for staining, allowing real-time tracking of events like centrosome movement. Phase-contrast microscopy enhances contrast in transparent specimens by exploiting differences in refractive index, facilitating visualization of chromosome condensation and centrosome separation during early prophase.^[16] DIC, which uses polarized light to highlight optical path gradients, provides pseudo-three-dimensional images with higher resolution and reduced artifacts compared to phase-contrast, making it ideal for monitoring centrosome migration in mitotic cells.^[17] However, both methods are limited by the diffraction of light, with a typical resolution of approximately 200 nm, preventing visualization of finer structures like individual microtubules. Fluorescence microscopy offers enhanced specificity for studying prophase through targeted labeling of proteins involved in spindle formation. Confocal fluorescence microscopy achieves optical sectioning for three-dimensional imaging, enabling detailed reconstruction of early spindle assembly and centrosome positioning in prophase.^[18] Super-resolution techniques, such as stimulated emission depletion (STED) microscopy, surpass the diffraction limit to resolve structures at 40-50 nm, allowing observation of microtubule organization during prophase spindle initiation.^[19] Time-lapse fluorescence imaging complements these by quantifying the duration of prophase events, such as centrosome separation, typically lasting 20-30 minutes in mammalian cells.^[20] Electron microscopy provides ultrastructural insights into prophase that surpass light-based methods. Transmission electron microscopy (TEM) reveals fine details of kinetochore formation in late prophase, including the layered organization of kinetochore proteins on centromeric chromatin, with resolutions down to 1-2 nm.^[21] Scanning electron microscopy (SEM), particularly serial block-face variants, offers surface views of spindle architecture, highlighting microtubule attachments and pole organization emerging in prophase.^[22] These fixed-sample techniques often integrate with staining for contrast enhancement, as detailed in related preparatory methods. As of 2025, cryogenic electron microscopy (cryo-EM) has advanced structural biology of prophase by providing atomic-level views of condensin complexes within chromosomes. Cryo-EM structures of condensin II bound to regulatory proteins like M18BP1 illustrate how these SMC complexes drive initial chromosome compaction in prophase, resolving subunit interactions at 3-4 Å resolution.^[23] Recent cryo-correlative light-electron microscopy (cryo-CLEM) workflows further enable in situ imaging of condensin distribution in near-native mitotic chromosomes, revealing helical architectures that underpin prophase folding.^[24]

Mitotic Prophase

Chromosome Condensation

During mitotic prophase, chromosomes undergo a dramatic transition from diffuse, extended chromatin fibers in interphase to compact, rod-like structures, enabling their alignment and segregation in subsequent mitotic stages. This compaction process involves two primary mechanisms: loop extrusion, where chromatin loops are actively formed and enlarged, and axial shortening, which reduces the overall length of the chromosome scaffold. Loop extrusion is primarily driven by the condensin complexes, which translocate along DNA to extrude loops, thereby organizing chromatin into a hierarchical, nested structure that achieves significant compaction without tangling. Axial shortening complements this by contracting the chromosome axis, facilitated by the resolution of topological constraints.^[25] The condensin I and II complexes are central to this process, each consisting of SMC2 and SMC4 ATPase subunits along with non-SMC regulatory components. Condensin II initiates compaction in early prophase within the intact nucleus, forming larger loops (approximately 300–400 kb) that establish the initial axial organization, while condensin I contributes later, after nuclear envelope breakdown, to refine the structure with smaller, more dynamic loops. These complexes are activated through phosphorylation by cyclin B-CDK1 at the G2/M transition; for instance, CDK1 phosphorylates the CAP-D3 subunit of condensin II at threonine 1415, recruiting Polo-like kinase 1 (Plk1) for further hyperphosphorylation and enhanced activity. Topoisomerase IIα plays a crucial role in resolving DNA entanglements and catenanes generated during loop extrusion, preventing structural defects and promoting axial contraction.^[25]^[26]^[27] Regulation of chromosome condensation is tightly coordinated by mitotic kinases. Cyclin B-CDK1 activation triggers the initial phosphorylation events, ensuring timely progression into prophase, while histone modifications further facilitate compaction. Phosphorylation of histone H3 at serine 10 (H3S10ph), primarily mediated by Aurora B kinase, correlates directly with the onset of condensation, promoting local chromatin compaction and aiding condensin recruitment by altering nucleosome interactions. This modification spreads along chromosome arms during prophase, enhancing overall structural rigidity.^[25]80718-7)^[28] As a result of these mechanisms, interphase chromatin, which can span meters in length for the human genome, compacts approximately 10,000-fold to form discrete, visible chromosomes under light microscopy, each consisting of two sister chromatids aligned along their length. This compaction not only makes chromosomes manageable for the mitotic spindle but also ensures their structural integrity for faithful segregation. Defects in condensin function or topoisomerase II activity lead to undercondensed chromosomes and segregation errors, underscoring the precision of this prophase event.^[25]^[26]

Centrosome Migration

Centrosome duplication initiates during the S phase of the cell cycle, where the existing pair of centrioles within each centrosome serves as templates for the formation of new daughter centrioles, resulting in each centrosome containing two centrioles by the end of G2 phase.^[29] However, full maturation of these duplicated centrosomes, involving the recruitment and expansion of pericentriolar material (PCM), occurs primarily during prophase, enhancing their microtubule-nucleating capacity to support spindle assembly.^[30] This maturation process ensures that the centrosomes are competent to organize microtubules effectively as mitosis progresses. During prophase, the matured centrosomes undergo separation and migration to opposite sides of the intact nuclear envelope, a microtubule-driven process essential for establishing spindle bipolarity.^[31] This movement is powered by motor proteins, including the plus-end-directed kinesin-5 family member Eg5, which generates outward sliding forces along interpolar microtubules to push the centrosomes apart, and the minus-end-directed dynein, which anchors to the nuclear envelope and pulls centrosomes toward the poles via astral microtubules. Dynein-mediated traction, in particular, initiates the initial separation in late G2/early prophase, cooperating with Eg5 to achieve robust migration. As centrosomes migrate, their positioning establishes the bipolar axis for the mitotic spindle, with the distance between them increasing from approximately 1-2 μm at the onset of prophase to 5-10 μm by the transition to prometaphase.^[32] This separation is critical for proper spindle pole organization and chromosome alignment in subsequent stages.^[31] The process is tightly regulated by kinases such as polo-like kinase 1 (PLK1) and Aurora A, which phosphorylate components of the γ-tubulin ring complex (γ-TuRC), including adaptor proteins like NEDD1, to activate microtubule nucleation sites at the centrosomes and facilitate PCM expansion.^[33] PLK1 acts upstream, phosphorylating pericentrin to initiate maturation, while Aurora A further enhances γ-TuRC docking and activity through targeted phosphorylations.

Mitotic Spindle Formation

During mitotic prophase, the spindle apparatus begins to assemble through two primary pathways: centrosome-mediated microtubule nucleation and chromatin-mediated microtubule generation. In the centrosome-mediated pathway, the pericentriolar material at the centrosomes, which have migrated to opposite poles of the cell, acts as the main microtubule-organizing center, where γ-tubulin ring complexes (γ-TuRCs) nucleate microtubules from their minus ends. This process establishes the initial framework for spindle bipolarity, with centrosomes serving as dominant sites for microtubule organization in most animal cells. Complementing this, the chromatin-mediated pathway operates via a Ran-GTP gradient generated around condensing chromosomes by the chromatin-bound guanine nucleotide exchange factor RCC1, which releases spindle assembly factors from importin inhibition. A key effector in this pathway is TPX2, which, upon Ran-GTP-mediated activation, binds to microtubules and promotes their nucleation and stabilization near chromatin, ensuring robust spindle formation even if centrosomal function is compromised. The mitotic spindle comprises three main types of microtubules, each contributing distinct structural and functional roles. Astral microtubules emanate from the spindle poles and extend toward the cell cortex, where they interact with the actin cytoskeleton to position and orient the spindle. Kinetochore microtubules, also known as k-fibers, originate from the poles and target the kinetochores on condensed chromosomes, facilitating their eventual capture and alignment. Interpolar microtubules extend between the two spindle poles, overlapping in the midzone to provide structural support and enable pole separation. Microtubule dynamics within the forming spindle are regulated by motor proteins and stabilizers that ensure proper length, orientation, and turnover. Kinesin-13 family members, such as MCAK and Kif2a, function as depolymerases by binding to microtubule ends and catalyzing tubulin subunit removal, which helps focus microtubules at poles and corrects erroneous attachments. In contrast, end-binding protein 1 (EB1) tracks growing microtubule plus ends as part of +TIP complexes, recruiting additional stabilizers and promoting dynamic instability essential for spindle exploration and chromosome capture. TPX2 further enhances nucleation by recruiting Aurora A kinase to activate microtubule polymerization factors, amplifying chromatin-induced assembly. Bipolarity of the spindle is established and maintained through the action of kinesin-5 motors, such as Eg5, which form bipolar minifilaments that crosslink and slide antiparallel interpolar microtubules, generating outward forces that push the poles apart. Inhibition of Eg5 leads to monopolar spindle formation, underscoring its critical role in preventing collapse and ensuring proper chromosome segregation. This motor-driven expansion synergizes with the nucleation pathways to create a focused, bipolar structure by prometaphase.

Nucleolar Disassembly

During mitotic prophase, nucleolar disassembly initiates the dissolution of this subnuclear structure, beginning with the fragmentation of nucleoli into smaller granular and fibrillar components that disperse around condensing chromosomes. This process is tightly regulated and precedes full nuclear envelope breakdown, ensuring the orderly transition to prometaphase. Concurrently, ribosomal RNA (rRNA) synthesis halts as cyclin-dependent kinase 1 (CDK1) in complex with cyclin B phosphorylates key components of the RNA polymerase I (Pol I) initiation complex, such as the selectivity factor SL1, thereby repressing transcription of rDNA loci.^[34]^[35] Central to this disassembly are the relocation and modification of nucleolar proteins, including nucleolin and fibrillarin, which are released from their organized structures and sequestered into a perichromosomal compartment. Nucleolin, a major nucleolar phosphoprotein, undergoes phosphorylation that disrupts its interactions within the granular component, while fibrillarin, a key methyltransferase in the fibrillar center, dissociates following the initial loss of Pol I subunits. Additionally, CDK1 phosphorylates lamins A and C in the nuclear lamina, weakening its structural integrity and facilitating partial envelope destabilization without complete breakdown at this stage.^[35]^[34]90471-P) Nucleolar disassembly typically begins in mid-prophase, shortly after the onset of chromosome condensation, and progresses over approximately 30 minutes in human cells like HeLa, completing by early prometaphase just before or during nuclear envelope breakdown. In some cell types, this process is reversible if mitotic progression is halted, allowing partial reassembly upon CDK1 inactivation. The primary function of nucleolar disassembly is to liberate ribosomal DNA loci on chromosomes, enabling their proper alignment and segregation by the mitotic spindle; disruptions in this process contribute to nucleolar stress, which is implicated in ribosomopathies such as Diamond-Blackfan anemia through impaired ribosome biogenesis.^[34]^[35]^[36]01146-1)

Meiotic Prophase I

Leptotene Stage

The leptotene stage marks the onset of meiotic prophase I, during which chromosomes begin to condense from their extended interphase configuration into visible thin, thread-like structures along the nuclear envelope. This initial condensation facilitates the organization of chromatin into linear arrays, setting the stage for subsequent homologous interactions in meiosis.^[37] A key event in leptotene is the assembly of axial elements (AEs), which form as fibrous cores along the length of each chromosome between sister chromatids. These AEs are primarily composed of meiosis-specific proteins SYCP2 and SYCP3, which polymerize to create a scaffold that recruits cohesin complexes and organizes chromatin loops. The formation of AEs begins as short linear segments that elongate and fuse, providing structural integrity to the condensing chromosomes.^[38]^[39]^[40] Concomitant with AE assembly, the SPO11 enzyme catalyzes the formation of numerous DNA double-strand breaks (DSBs), approximately 200–300 per meiosis in mammals such as mice, to initiate recombination processes. These DSBs occur preferentially at hotspots along the chromosome axes and are essential for promoting genetic diversity. As chromosomes elongate along the forming axis during this stage, telomeres attach to and cluster at specific sites on the nuclear envelope, forming the bouquet configuration observed in many organisms including yeast and mammals. This clustering aids in the spatial organization of chromosome ends.^[41]^[42]^[43] The duration of leptotene varies significantly across species, lasting several hours in budding yeast but extending to days in mammalian germ cells, reflecting differences in meiotic progression rates. A regulatory checkpoint monitors DSB formation during leptotene; insufficient breaks, as seen in SPO11 mutants, can delay advancement to later stages by activating DNA damage response pathways.^[6]^[44]

Zygotene Stage

The zygotene stage represents the second substage of meiotic prophase I, during which homologous chromosomes actively search for and begin pairing with each other, initiating the process of synapsis essential for genetic recombination and proper segregation. This stage follows leptotene, where double-strand breaks (DSBs) are induced by SPO11 to facilitate homology recognition, and is characterized by dynamic chromosome movements that promote alignment between maternal and paternal homologs.^[45]^[46] Homologous chromosome pairing during zygotene is guided by a telomere-led bouquet configuration, in which telomeres cluster at the nuclear envelope, facilitating initial alignment through rapid, cytoskeleton-mediated movements that bring distant chromosomal regions into proximity.^[47] Complementing this structural organization, DSBs generated in leptotene are processed into single-stranded DNA overhangs that invade homologous sequences via strand invasion, stabilizing early interhomolog interactions and directing precise homolog search across the genome.^[48]^[46] Synapsis begins with the assembly of the synaptonemal complex (SC), a proteinaceous structure that zips together the lateral elements of homologous chromosome axes. Initiation involves the central element component SYCP1, which polymerizes between the axes to form a scaffold, while transverse filaments extend from SYCP1 to physically connect and stabilize the paired homologs, progressively elongating the SC from sites of initial contact.^[49]^[50] By late zygotene, synapsis is partial, with approximately 50-80% of chromosome axes engaged in pairing in mammalian spermatocytes, leaving regions of asynapsis that are monitored to ensure overall fidelity.^[51] Persistent asynapsis in germ cells activates apoptotic pathways, eliminating defective cells to prevent aneuploid gametes and maintain reproductive integrity.^[52]^[53] Regulation of zygotene progression relies on HORMAD1 and HORMAD2 proteins, which localize to and stabilize unpaired chromosome regions, enabling surveillance by meiotic checkpoints that detect homology defects and coordinate DSB processing for successful pairing.^[48]^[54] These proteins recruit ATR kinase to unsynapsed axes, phosphorylating targets like H2AX to signal potential errors and halt progression if synapsis remains incomplete.^[55]

Pachytene Stage

The pachytene stage represents the third substage of meiotic prophase I, during which synapsis between homologous chromosomes is fully completed following initiation in the preceding zygotene stage. At this point, the synaptonemal complex (SC) achieves complete assembly, with the lateral elements of sister chromatids fully connected by the central region, forming a tripartite structure that stabilizes homologous chromosome pairing along their entire length.^[49] This full synapsis is essential for the progression of recombination events, ensuring proper alignment and facilitating genetic exchange. Meiotic recombination peaks during pachytene, where double-strand breaks (DSBs) induced earlier by SPO11 are repaired through homologous recombination. Strand invasion by the RAD51/DMC1 nucleoprotein filament forms a D-loop intermediate on the homologous chromosome, leading to the capture of the second end and formation of double Holliday junctions.^[56] A subset of these intermediates is resolved into class I crossovers, marked by the MutLγ complex (MLH1/MLH3), which ensures interference—a regulatory mechanism that promotes an even distribution of crossovers, typically resulting in approximately 40-90 crossovers per human meiosis depending on sex.^[57]^[58] The pachytene checkpoint actively monitors SC integrity and recombination proficiency, arresting or eliminating cells with defects in synapsis or crossover formation to prevent aneuploid gametes. Failure to satisfy this checkpoint, often due to asynapsis or unresolved recombination intermediates, triggers apoptosis and is a common cause of infertility in both males and females.^[59]^[60] Transcription during pachytene is spatially regulated, with active gene expression in autosomes supporting meiotic progression, while the X and Y chromosomes condense into the XY body—a heterochromatic domain where meiotic sex chromosome inactivation (MSCI) silences most genes via the mechanism of meiotic silencing of unsynapsed chromatin (MSUC).^[61] This silencing prevents expression of X- and Y-linked genes, which could otherwise disrupt meiosis, and is enforced by histone modifications and recruitment of repressive factors to the asynapsed sex chromosomes.^[62]

Diplotene Stage

The diplotene stage represents the fourth substage of meiotic prophase I, during which the central region of the synaptonemal complex (SC) begins to dissolve, allowing homologous chromosomes to separate along most of their length while remaining physically linked at chiasmata sites. This partial disassembly of the SC, initiated by phosphorylation events involving kinases such as Polo-like kinase 1 (PLK1), marks the transition from full synapsis to a more desynapsed state, with the lateral elements persisting longer than the central region.^[63] Concurrently, chromosomes undergo further shortening and thickening, enhancing their visibility as bivalents under microscopy.^[64] Chiasmata, the cytological manifestations of crossovers that formed earlier during pachytene, become prominently visible in diplotene as X-shaped structures where sister chromatids of homologous chromosomes appear to cross. These structures stabilize the homologs against repulsion forces, preventing premature separation and ensuring proper alignment during metaphase I, where they ultimately resolve into functional crossovers that facilitate chromosome segregation.^[63] In mammalian oocytes, the diplotene stage leads to a prolonged arrest known as the dictyotene stage, where meiosis pauses for extended periods—ranging from weeks in mice to decades in humans—until hormonal signals trigger resumption.^[64] During this arrest, chromatin undergoes remodeling, including partial decondensation and transcriptional activity, which supports oocyte growth, viability, and preparation for subsequent meiotic progression.^[65] The locked-in chiasmata at diplotene ensure that recombination events promote genetic diversity by enabling the exchange of alleles between homologous chromosomes, which, combined with independent assortment, generates novel genetic combinations essential for evolutionary adaptability.

Diakinesis Stage

Diakinesis is the terminal substage of meiotic prophase I, during which chromosomes undergo maximal compaction, resulting in highly shortened and thickened structures that facilitate their visualization and alignment for subsequent division. The bivalents, formed by paired homologous chromosomes connected at chiasmata, achieve their most condensed state, with each bivalent appearing as a compact unit. In human germ cells, 23 such bivalents are present, ensuring that recombination events from earlier stages are stabilized for proper segregation.^[3]^[66] Concomitant with this chromosomal shortening, the nuclear envelope exhibits initial fenestration, characterized by localized fragmentation or partial disassembly, particularly at the poles, which prepares the cell for spindle formation. Nucleoli are absent at this stage, having fully disassembled earlier in prophase I to support the metabolic shifts required for meiosis. These nuclear changes occur while the bivalents reposition near the nuclear periphery, promoting even distribution.^[67]^[68]^[3] The diakinesis stage is notably brief, often lasting only minutes in various species, before transitioning directly to metaphase I as the nuclear envelope fully breaks down. This short duration underscores its role as a preparatory phase, where a checkpoint mechanism verifies the integrity of chiasmata across all bivalents to prevent progression with defective recombination structures.^[69]^[70]

Meiotic Prophase II

Characteristics and Events

Prophase II initiates following the brief interkinesis after cytokinesis of meiosis I, in two haploid daughter cells. Each cell contains a haploid set of chromosomes, consisting of 23 chromosomes in humans, where each chromosome is composed of two sister chromatids that may have partially decondensed during interkinesis. During this stage, the chromosomes recondense to facilitate their alignment and segregation in the subsequent division. Unlike prophase I, prophase II lacks homologous recombination or synapsis, resembling a mitotic prophase in its simplicity.^[71]^[72]^[73] A key event in prophase II is the reformation of the mitotic spindle apparatus. In cells equipped with centrosomes, such as spermatocytes, the centrosomes—which have duplicated during the preceding interkinesis—migrate to opposite poles, nucleating microtubules to form a new bipolar spindle. In contrast, oocytes in many species, including humans and mice, assemble an acentrosomal spindle, primarily through chromatin-induced microtubule nucleation and stabilization by motor proteins and microtubule-associated proteins. This process ensures proper bipolar organization despite the absence of centrosomal organizing centers.^[5]^[74] The nuclear envelope undergoes rapid breakdown during prophase II, fragmenting into vesicles and allowing direct interaction between chromosomes and spindle microtubules. This disassembly occurs in cells of reduced volume compared to the original meiotic cell, reflecting the post-meiosis I division. Prophase II is notably brief in duration, varying by organism but generally much shorter than prophase I, underscoring its streamlined role in equational division without additional genetic exchange. These events parallel those in mitotic prophase but adapt to the haploid context of meiosis II.^[5]^[75]

Comparison to Mitotic Prophase

Meiotic prophase II shares key mechanistic similarities with mitotic prophase, particularly in chromosome condensation and spindle assembly. In both processes, chromosomes condense through the action of condensin complexes, which organize chromatin into compact structures to facilitate segregation; for instance, condensin II localizes to chromosome axes in prophase II, promoting compaction similar to its role in mitotic prophase where it initiates axial shortening before nuclear envelope breakdown.^[76] Spindle assembly pathways also overlap, involving microtubule nucleation and organization around chromosomes or centrosomes to form the bipolar apparatus essential for alignment.^[77] Despite these parallels, prophase II differs markedly from mitotic prophase in several adaptations suited to post-reductional division. Unlike mitotic prophase, which can occur in diploid cells with full DNA replication preceding it, prophase II lacks double-strand breaks (DSBs) and synapsis, as these recombination events are confined to prophase I; instead, prophase II focuses on recondensing already recombinant haploid chromosomes without further pairing.^[77] It is typically shorter in duration than mitotic prophase in many species, reflecting its streamlined role without extended recombination.^[78] Additionally, in female meiosis, prophase II often proceeds via acentrosomal spindle assembly, relying on chromatin-mediated microtubule organization rather than centrosome-driven pathways common in mitotic prophase of somatic cells.^[74] Evolutionarily, prophase II appears to have arisen as a mitotic-like reset following the specialized complexity of prophase I, enabling an equational division that halves sister chromatids without altering ploidy further.^[79] This adaptation ensures the accurate segregation of recombinant chromosomes generated in meiosis I, minimizing errors in gamete formation and preserving genetic diversity.^[80]

Regulation and Arrest

Prophase I Arrest Mechanisms

In mammalian oocytes, prophase I arrest occurs at the dictyotene (or dictyate) stage following the diplotene substage, a prolonged quiescence that begins in fetal ovaries and persists from birth until ovulation, potentially lasting up to 50 years in humans.^[81]^[82]^[83] This arrest maintains the oocyte in a germinal vesicle (GV) state, preventing progression to metaphase I until hormonal signals trigger resumption.^[84] The primary mechanism sustaining dictyotene arrest involves elevated intracellular cyclic AMP (cAMP) levels, which inhibit maturation-promoting factor (MPF) activity. The G-protein-coupled receptor GPR3 constitutively activates adenylyl cyclase in the oocyte, ensuring persistent cAMP production that activates protein kinase A (PKA); PKA in turn phosphorylates targets to suppress CDK1 (cyclin-dependent kinase 1) activation by inhibiting CDC25B phosphatase and enhancing WEE1/MYT1 kinases, which add inhibitory phosphates to CDK1.^[85]^[83]^[86] Additionally, the anaphase-promoting complex/cyclosome (APC/C) associated with CDH1 continuously degrades cyclin B1, further preventing MPF assembly and CDK1 activation during this phase.^[87]^[88] A parallel surveillance system relies on the DNA damage response (DDR) pathway, where ATM and ATR kinases detect unrepaired double-strand breaks (DSBs) from meiotic recombination; if DSBs exceed a threshold (approximately 10 unrepaired lesions), ATM activates CHK2, triggering p53-dependent apoptosis or elimination of defective oocytes to ensure genomic integrity.^[89]^[90]^[91] This DDR mechanism enforces arrest or elimination specifically in prophase I-arrested oocytes, contrasting with more efficient repair in mitotic cells.^[92] The dictyotene arrest serves to facilitate oocyte growth within follicles, enabling the accumulation of maternal mRNAs, proteins, and organelles essential for fertilization and early embryonic cleavage before zygotic genome activation.^[93] Premature release from this arrest, such as due to hormonal dysregulation, leads to oocyte atresia, where follicles degenerate and viable gametes are lost, contributing to the limited ovarian reserve.^[94] This long-term arrest is female-specific, occurring in fetal and postnatal oocytes but absent in males, where spermatocytes complete prophase I and proceed through meiosis without prolonged quiescence, reflecting sex-dimorphic timing in gametogenesis.^[95]^[96]^[97]

Cell Cycle Checkpoints

Cell cycle checkpoints during prophase serve as critical surveillance mechanisms to ensure the fidelity of chromosome condensation, early spindle formation, and DNA integrity before progression to prometaphase in both mitotic and meiotic divisions. In mitosis, the antephase checkpoint, operating at the G2/M transition and into early prophase, monitors for chromosome damage and stress signals to prevent premature mitotic commitment. Similarly, in meiosis, these checkpoints oversee the processing of programmed double-strand breaks (DSBs) essential for recombination while averting progression with unresolved genomic issues. These mechanisms collectively maintain genomic stability by delaying or reversing prophase events if fidelity is compromised.^[98] Precursors to the spindle assembly checkpoint (SAC) initiate in prophase by recruiting key proteins such as Mad2 and BubR1 to kinetochores, where they begin monitoring initial microtubule attachments and tension. Mad2 localizes to unattached kinetochores during early mitosis, forming a template for SAC activation, while BubR1 synergizes with Mad2 to inhibit the anaphase-promoting complex/cyclosome (APC/C), thereby restraining premature sister chromatid separation. This early surveillance in prophase ensures proper kinetochore-spindle interactions before nuclear envelope breakdown, reducing errors in chromosome alignment. In meiosis, analogous SAC components function during prophase II to safeguard post-recombination segregation.^[99]^[100] The DNA damage checkpoint, mediated by the ATM/CHK2 pathway, halts prophase progression if DSBs persist or chromosome condensation fails. In mitosis, ATM detects DNA lesions and activates CHK2 to enforce G2/M arrest, preventing entry into prophase with unrepaired damage that could lead to condensation defects. In meiosis, during prophase I, ATM/CHK2 signaling responds to unrepaired recombination-induced DSBs, triggering oocyte elimination via p53-dependent apoptosis if repair thresholds are exceeded, such as in cases with over 10 persistent DSBs. This checkpoint ensures DSB resolution before meiotic progression, distinct from prolonged arrests in oocytes detailed elsewhere.00845-5)^[91] Activation of these checkpoints involves inhibitory phosphorylation of CDK1 by Wee1 kinase on tyrosine 15, maintaining low CDK1 activity to block prometaphase entry until prophase conditions are satisfied; upon resolution, Cdc25 phosphatases counteract Wee1, releasing CDK1 to drive nuclear envelope breakdown. Bypass of prophase checkpoints, such as through Wee1 or SAC component dysregulation, results in chromosome missegregation and aneuploidy, a hallmark of genomic instability. Therapeutically, targeting these pathways—such as with Wee1 inhibitors—exploits cancer cells' reliance on faulty checkpoints, inducing mitotic catastrophe and enhancing chemotherapy efficacy in tumors with checkpoint defects.^[101]^[102]

Variations Across Cell Types

Differences in Animal Cells

In animal cells, prophase is characterized by a strong reliance on centrosomes for organizing the microtubule-based spindle apparatus, a feature absent in plant cells that instead utilize decentralized microtubule nucleation sites. Centrosomes, which consist of a pair of centrioles surrounded by pericentriolar material (PCM), undergo duplication during the preceding S phase but mature and separate during prophase to establish spindle polarity. This separation is driven by microtubule motor proteins such as kinesin-5 (Eg5), which push the centrosomes apart, and dynein, which facilitates their migration to opposite sides of the nucleus. In meiotic prophase I of male germ cells, such as mouse spermatocytes, centrosome migration initiates at the diplotene stage, ensuring bipolar spindle formation for proper chromosome segregation. Polo-like kinase 1 (PLK1) plays a critical role in this process by regulating PCM assembly and centrosome disjunction, with its inhibition leading to monopolar spindles and meiotic arrest. This centrosome-dependent mechanism contrasts with acentrosomal pathways in other systems and is essential for the fidelity of division in animal somatic and germ cells.^[103] Preparation for cytokinesis also begins in late prophase of animal cells, with initial accumulation and reorganization of contractile ring components, including actin filaments and non-muscle myosin II, contributing to cell rounding and cortical stiffening. Myosin II progressively accumulates at the cell cortex during prophase to drive mitotic cell rounding, a process mediated by cyclin-dependent kinase 1 (CDK1) phosphorylation of myosin regulatory light chain, which disassembles stress fibers and increases cortical tension in preparation for subsequent furrow ingression. Actin polymerization, facilitated by formins, supports this cortical remodeling, setting the stage for the equatorial positioning of the contractile ring later in mitosis or meiosis. Although full contractile ring constriction occurs in anaphase, these early prophase events ensure the timely recruitment of RhoA-GTPase effectors like ROCK, which activate myosin II contractility at the division site. In female animal germ cells, prophase exhibits unique adaptations, particularly in oocytes where meiosis is acentrosomal, lacking functional centrosomes due to their elimination or inactivation during oogenesis. Spindle assembly in these cells relies instead on chromatin-mediated microtubule nucleation and motor-driven sorting of microtubules into bipolar arrays, a process that begins in prophase I but is more error-prone than centrosomal mechanisms. Mammalian oocytes, for instance, arrest in prophase I (dictyate stage) for extended periods—up to decades in humans—allowing oocyte growth and DNA repair while preventing premature progression; this arrest is maintained by high cAMP levels and inhibitory phosphorylation of CDK1. Resumption of meiosis upon hormonal stimulation highlights the prolonged nature of this phase, which contrasts with the shorter prophase in male meiosis. Variations in prophase checkpoint stringency are evident across animal model organisms, influencing meiotic progression and error correction. In Drosophila oocytes, the DNA damage checkpoint during early prophase I is less stringent than in mammals, mediated by the Chk2 homolog (Loki), which is required for arrest and elimination in response to double-strand breaks but allows rapid progression of healthy oocytes despite potential recombination errors.^[104] In contrast, mammalian oocytes enforce stricter synapsis and recombination checkpoints in prophase I, mediated by ATM/ATR kinases, which delay progression if homologous chromosomes fail to pair or repair, reducing aneuploidy risks but extending arrest duration. These differences reflect evolutionary adaptations to germline demands, with Drosophila prioritizing speed in oogenesis and mammals emphasizing fidelity in prolonged oocyte maturation.

Differences in Plant Cells

Plant cells lack centrosomes, relying instead on acentrosomal mechanisms for microtubule organization during prophase, which contrasts with the centrosome-dependent pathways predominant in animal cells. Microtubule nucleation occurs primarily at the nuclear envelope and cortical regions, facilitated by γ-tubulin ring complexes (γ-TuRCs) that associate with the envelope to generate microtubules for the forming prospindle. This acentrosomal setup allows for flexible, distributed microtubule assembly tailored to the immobile, walled architecture of plant cells. A hallmark of plant prophase is the formation of the preprophase band (PPB), a transient cortical ring of bundled microtubules and actin filaments that encircles the nucleus and precisely marks the plane of future cell division. The PPB, which assembles in late G2/early prophase, predicts the cytokinetic site by interacting with the plasma membrane and cell wall components, ensuring the subsequent phragmoplast aligns correctly for cell plate insertion. This structure disassembles shortly before nuclear envelope breakdown but leaves a biochemical memory in the cortex to guide spindle positioning and cytokinesis. The PPB's role underscores the cell wall's influence, as the rigid extracellular matrix fixes cell geometry and demands accurate division plane specification to avoid structural damage.^[105] Preparation for spindle formation in plant prophase emphasizes chromatin-mediated pathways, bypassing the need for centrioles present in animals. Chromatin generates a localized Ran-GTP gradient via the guanine nucleotide exchange factor RCC1, which releases spindle assembly factors like TPX2 from importin inhibition, promoting microtubule nucleation and organization around chromosomes. This pathway drives the transition from prospindle microtubules—initially nucleated at the nuclear envelope—to a bipolar mitotic spindle post-envelope breakdown, ensuring chromosome alignment without centralized MTOCs. In Arabidopsis thaliana, a dicot model, Ran-GTP dominantly regulates TPX2-dependent microtubule nucleation during prophase, facilitating prospindle assembly before metaphase onset.^[106] The rigid cell wall profoundly shapes prophase dynamics by constraining cell shape changes, extending the phase's duration relative to animal cells to accommodate microtubule reorganization and PPB maturation without cellular rounding. This adaptation prepares for phragmoplast-mediated cytokinesis, where a new cell plate forms centrally rather than via furrowing, maintaining wall integrity across daughter cells. Such wall-imposed constraints highlight prophase as a critical preparatory stage in plants, integrating cytoskeletal cues with extracellular rigidity.^[107] Mechanisms of prophase microtubule organization show conservation between dicots and monocots, though subtle variations exist in nucleation efficiency and PPB stability. For instance, in the monocot Oryza sativa (rice), the chromatin-dependent Ran-GTP pathway similarly establishes bipolar spindles, but proteins like OsMTOPVIB enhance microtubule pole focusing during prophase, potentially adapting to larger cell sizes in grasses compared to the compact meristems of dicots like Arabidopsis. These differences reflect evolutionary divergences in cell wall composition and tissue architecture, yet the core acentrosomal reliance remains uniform across angiosperms.^[106]

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The Onset of Meiotic Prophase. The onset and regulation of meiosis differ significantly between male and female mice (Figure 1; Handel and Eppig, 1998). Oocyte ...
[97]
Transcriptional progression during meiotic prophase I reveals sex ...
Sep 9, 2021 · During fetal development, female gem cells go through 4 stages of meiotic prophase I (leptotene, zygotene, pachytene and diplotene) and at ...
[98]
Safeguarding Entry into Mitosis: the Antephase Checkpoint - PMC
The antephase checkpoint prevents cells from entering mitosis in response to stress, delaying entry and promoting reversal of chromosome condensation.
[99]
Mammalian mad2 and bub1/bubR1 recognize distinct spindle ...
A number of proteins, including mad2, bub1, and bubR1, have been implicated in the metaphase checkpoint control in mammalian cells. Metaphase checkpoints have ...
[100]
Checkpoint Protein BubR1 Acts Synergistically with Mad2 to Inhibit ...
APC is also negatively regulated by two checkpoint proteins, Mad2 and BubR1. When the spindle assembly checkpoint is activated, Mad2 binds to Cdc20 and inhibits ...
[101]
Mitotic progression becomes irreversible in prometaphase and ... - NIH
Cdk1 activity increases sharply during prophase and prometaphase. It is well established that the activity of Cdk1/cyclin B complex is low in interphase and ...
[102]
Cell cycle checkpoint in cancer: a therapeutically targetable double ...
Sep 27, 2016 · In this review we summarize developing concepts on how targeting cell cycle checkpoints may provide substantial improvement to cancer therapy.
[103]
Cytoplasmic MTOCs control spindle orientation for asymmetric cell ...
Oct 2, 2017 · This study identifies spindle orientation as a conserved factor in land plants to assist division plane orientation.
[104]
OsMTOPVIB is required for meiotic bipolar spindle assembly - PNAS
Jul 24, 2019 · The organization of microtubules into a bipolar spindle is essential for chromosome segregation. Both centrosome and chromatin-dependent ...
[105]
Proper division plane orientation and mitotic progression ... - PNAS
Feb 15, 2017 · Plant cells are surrounded by a cell wall that together with other cellular factors, controls cell growth and restricts cell movement.