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Endoreduplication
Endoreduplication
Endoreduplication
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Endoreduplication (also referred to as endoreplication or endocycling) is replication of the nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. Endoreduplication can be understood simply as a variant form of the mitotic cell cycle (G1-S-G2-M) in which mitosis is circumvented entirely, due to modulation of cyclin-dependent kinase (CDK) activity.[1][2][3][4] Examples of endoreduplication characterised in arthropod, mammalian, and plant species suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis of cell types that fulfill an array of biological functions.[1][2] While endoreduplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues.[5] Polyploidy and aneuploidy are common phenomena in cancer cells.[6] Given that oncogenesis and endoreduplication likely involve subversion of common cell cycle regulatory mechanisms, a thorough understanding of endoreduplication may provide important insights for cancer biology.

Examples in nature

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Endoreduplicating cell types that have been studied extensively in model organisms

Organism Name Cell type Biological function Citation
fly Drosophilia Melanogaster larval tissues (incl. salivary glands) secretion, embryogenesis [7]
fly ovarian follicle, nurse cells nourishment, protection of oocytes [8]
rodent megakaryocyte platelet formation [9]
rodent hepatocyte regeneration [10]
rodent trophoblast giant cell placental development, nourishment of embryo [11]
plant Arabidopsis Thaliana trichome defense from herbivory, homeostasis [12]
plant leaf epidermal cell leaf size, structure [13]
plant endosperm nourishment of embryo [14]
nematode Caenorhabditis elegans hypodermis secretion, body size [15]
nematode intestine unknown [16]

Endoreduplication, endomitosis and polytenization

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Endoreduplication, endomitosis and polytenization are three different processes resulting in polyploidization of a cell in a regulated manner. In endoreduplication cells skip M phase completely by exiting the mitotic cell cycle in the G2 phase after completing the S phase several times, resulting in a mononucleated polyploid cell. The cell ends up with twice as many copies of each chromosome per repeat of the S phase.[17] Endomitosis is a type of cell cycle variation where mitosis is initiated, but stopped during anaphase and thus cytokinesis is not completed. The cell ends up with multiple nuclei in contrast to a cell undergoing endoreduplication.[17][18] Therefore depending on how far the cell progresses through mitosis, this will give rise to a mononucleated or binucleated polyploid cell. Polytenization arises with under- or overamplification of some genomic regions, creating polytene chromosomes.[3][4]

Endocycling vs. endomitosis

Biological significance

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Based on the wide array of cell types in which endoreduplication occurs, a variety of hypotheses have been generated to explain the functional importance of this phenomenon.[1][2] Unfortunately, experimental evidence to support these conclusions is somewhat limited.

Cell differentiation

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In developing plant tissues the transition from mitosis to endoreduplication often coincides with cell differentiation and morphogenesis.[19] However it remains to be determined whether endoreduplication and polyploidy contribute to cell differentiation or vice versa. Targeted inhibition of endoreduplication in trichome progenitors results in the production of multicellular trichomes that exhibit relatively normal morphology, but ultimately dedifferentiate and undergo absorption into the leaf epidermis.[20] This result suggests that endoreduplication and polyploidy may be required for the maintenance of cell identity.

Cell/organism size

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Cell ploidy often correlates with cell size,[13][15] and in some instances, disruption of endoreduplication results in diminished cell and tissue size [21] suggesting that endoreduplication may serve as a mechanism for tissue growth. Relative to mitosis, endoreduplication does not require cytoskeletal rearrangement or the production of new cell membrane and it often occurs in cells that have already differentiated. As such it may represent an energetically efficient alternative to cell proliferation among differentiated cell types that can no longer afford to undergo mitosis.[22] While evidence establishing a connection between ploidy and tissue size is prevalent in the literature, contrary examples also exist.[19]

Oogenesis and embryonic development

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Endoreduplication is commonly observed in cells responsible for the nourishment and protection of oocytes and embryos. It has been suggested that increased gene copy number might allow for the mass production of proteins required to meet the metabolic demands of embryogenesis and early development.[1] Consistent with this notion, mutation of the Myc oncogene in Drosophila follicle cells results in reduced endoreduplication and abortive oogenesis.[23] However, reduction of endoreduplication in maize endosperm has limited effect on the accumulation of starch and storage proteins, suggesting that the nutritional requirements of the developing embryo may involve the nucleotides that comprise the polyploid genome rather than the proteins it encodes.[24]

Buffering the genome

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Another hypothesis is that endoreduplication buffers against DNA damage and mutation because it provides extra copies of important genes.[1] However, this notion is purely speculative and there is limited evidence to the contrary. For example, analysis of polyploid yeast strains suggests that they are more sensitive to radiation than diploid strains.[25]

Stress response

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Research in plants suggests that endoreduplication may also play a role in modulating stress responses. By manipulating expression of E2fe (a repressor of endocycling in plants), researchers were able to demonstrate that increased cell ploidy lessens the negative impact of drought stress on leaf size.[26] Given that the sessile lifestyle of plants necessitates a capacity to adapt to environmental conditions, it is appealing to speculate that widespread polyploidization contributes to their developmental plasticity

Genetic control of endoreplication

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The best-studied example of a mitosis-to-endoreduplication transition occurs in Drosophila follicle cells and is activated by Notch signaling.[27] Entry into endoreduplication involves modulation of mitotic and S-phase cyclin-dependent kinase (CDK) activity.[28] Inhibition of M-phase CDK activity is accomplished via transcriptional activation of Cdh/fzr and repression of the G2-M regulator string/cdc25.[28][29] Cdh/fzr is responsible for activation of the anaphase-promoting complex (APC) and subsequent proteolysis of the mitotic cyclins. String/cdc25 is a phosphatase that stimulates mitotic cyclin-CDK complex activity. Upregulation of S-phase CDK activity is accomplished via transcriptional repression of the inhibitory kinase dacapo. Together, these changes allow for the circumvention of mitotic entry, progression through G1, and entry into S-phase. The induction of endomitosis in mammalian megakaryocytes involves activation of the c-mpl receptor by the thrombopoietin (TPO) cytokine and is mediated by ERK1/2 signaling.[30] As with Drosophila follicle cells, endoreduplication in megakaryocytes results from activation of S-phase cyclin-CDK complexes and inhibition of mitotic cyclin-CDK activity.[31][32]

Notch regulation of endocycling

Entry into S-phase during endoreduplication (and mitosis) is regulated through the formation of a prereplicative complex (pre-RC) at replication origins, followed by recruitment and activation of the DNA replication machinery. In the context of endoreduplication these events are facilitated by an oscillation in cyclin E-Cdk2 activity. Cyclin E-Cdk2 activity drives the recruitment and activation of the replication machinery,[33] but it also inhibits pre-RC formation,[34] presumably to ensure that only one round of replication occurs per cycle. Failure to maintain control over pre-RC formation at replication origins results in a phenomenon known as "rereplication" which is common in cancer cells.[2] The mechanism by which cyclin E-Cdk2 inhibits pre-RC formation involves downregulation of APC-Cdh1-mediated proteolysis and accumulation of the protein Geminin, which is responsible for sequestration of the pre-RC component Cdt1.[35][36]

Oscillations in Cyclin E-Cdk2 activity are modulated via transcriptional and post-transcriptional mechanisms. Expression of cyclin E is activated by E2F transcription factors that were shown to be required for endoreduplication.[37][38][39] Recent work suggests that observed oscillations in E2F and cyclin E protein levels result from a negative-feedback loop involving Cul4-dependent ubiquitination and degradation of E2F.[40] Post-transcriptional regulation of cyclin E-Cdk2 activity involves Ago/Fbw7-mediated proteolytic degradation of cyclin E [41][42] and direct inhibition by factors such as Dacapo and p57.[43][44]

Premeiotic endomitosis in unisexual vertebrates

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The unisexual salamanders (genus Ambystoma) are the oldest known unisexual vertebrate lineage, having arisen about 5 million years ago.[45] In these polyploid unisexual females, an extra premeiotic endomitotic replication of the genome, doubles the number of chromosomes.[46] As a result, the mature eggs that are produced subsequent to the two meiotic divisions have the same ploidy as the somatic cells of the adult female salamander. Synapsis and recombination during meiotic prophase I in these unisexual females is thought to ordinarily occur between identical sister chromosomes and occasionally between homologous chromosomes. Thus little, if any, genetic variation is produced. Recombination between homeologous chromosomes occurs rarely, if at all.[46]

References

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Endoreduplication

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Endoreduplication is a specialized variant of the in which eukaryotic cells undergo repeated rounds of without intervening or , resulting in polyploid nuclei containing multiple copies of the genome. This process, also referred to as endoreplication or endocycling, produces cells with levels ranging from 4C to over 1000C, depending on the organism and tissue, and is evolutionarily conserved in and animals. It differs from standard proliferation by bypassing the M phase, allowing for genome amplification in terminally differentiated or metabolically demanding cells. The mechanism of endoreduplication involves an oscillation between G-phase (gap) and S-phase (DNA synthesis) activities, driven primarily by cyclin-dependent kinases (CDKs) and their regulators. Mitotic entry is inhibited through downregulation of mitotic cyclins by the anaphase-promoting complex/cyclosome (APC/C) and its cofactor Fizzy-related (Fzr/Cdh1), while S-phase progression is promoted by E2F transcription factors and cyclin E-CDK2 complexes. In plants, additional regulation occurs via phytohormones such as auxin, cytokinin, and gibberellin, as well as CDK inhibitors like ICK1 and SMR proteins, which fine-tune the extent of polyploidization. This self-limiting process ensures controlled polyploidy without uncontrolled rereplication. Endoreduplication is particularly prevalent in , where it drives developmental processes such as seed formation in (reaching up to 96C through 4-5 cycles) and differentiation in , enhancing cell expansion and . In animals, it occurs in specialized tissues like the salivary glands of Drosophila melanogaster (up to 1024C ploidy) and ovarian follicle cells (up to 16C ploidy) as well as giant cells in rodent placentas (exceeding 1000C). Mammalian examples include postnatal polyploidization in hepatocytes via endomitosis, supporting and metabolic demands. Biologically, endoreduplication facilitates rapid , elevated for transcription (e.g., metabolic enzymes), and to environmental stresses like in , without the need for . It plays critical roles in embryogenesis, nutrient allocation in seeds and fruits, and tissue , such as maintaining the blood-brain barrier in . However, dysregulation can contribute to , including and polyploid giant cancer cells (PGCCs) in tumors like liver (up to 54% ), which promote relapse and resistance. Emerging research highlights its untapped potential in for engineering stress-resilient crops through targeted induction.

Overview

Definition

Endoreduplication is a specialized variant of the cell cycle characterized by repeated rounds of DNA synthesis during the S-phase without subsequent mitosis or cytokinesis, leading to the formation of polytene or polyploid nuclei. This process allows cells to amplify their genomic content progressively, increasing the nuclear DNA amount while maintaining a single nucleus. In contrast to standard mitosis, endoreduplication omits key mitotic events such as spindle formation, chromosome condensation, and segregation, thereby avoiding the equitable distribution of replicated chromosomes into daughter cells. A related variant, endomitosis, involves an abortive mitosis but similarly results in polyploidy without full cell division. Through successive endocycles, levels typically escalate from the diploid 2C state to 4C, 8C, and higher, with extreme cases reaching up to 1024C in specialized tissues such as giant cells or certain nurse cells. This stepwise increase in DNA content—often in powers of two—enables substantial genomic amplification without the risks associated with chromosomal partitioning errors. The primary outcomes of endoreduplication include the development of enlarged nuclei and enhanced due to the elevated copy number of genes, which amplifies transcriptional output and supports heightened metabolic demands in terminally differentiated cells. This nuclear expansion correlates directly with ploidy level, promoting larger cell sizes and facilitating processes like rapid growth or resource accumulation.

Historical Context

The phenomenon of endoreduplication was initially observed through studies of polytene chromosomes in insect tissues during the late 19th and early 20th centuries. In 1881, Édouard Balbiani described giant, banded chromosomes in the salivary glands of chironomid larvae, marking one of the earliest reports of structures resulting from repeated without . However, the polytene nature of these chromosomes, indicative of endoreduplication, was not fully recognized until , when Emil Heitz and Hans Bauer provided detailed cytological analyses in and other dipterans, highlighting their formation via successive endomitotic cycles. These observations laid the groundwork for understanding endoreduplication as a developmental process that amplifies in specific tissues. The term "endoreduplication" was formally coined in 1953 by Albert Levan and Theodore S. Hauschka to describe of chromosomes without intervening , based on their cytogenetic studies of in ascites tumor cells. This nomenclature distinguished the process from other forms of , such as whole-genome duplication, and emphasized its occurrence in both normal and pathological contexts. Early experimental inductions of endoreduplication, often using to disrupt , further illuminated the process; for instance, Levan's 1938 work on root tips demonstrated colchicine-induced c-mitosis leading to polyploid nuclei, though without the specific term. In , cytological evidence for endoreduplication emerged prominently in the 1950s through analyses of endosperm tissues. H. Swift's 1950 quantitative measurements of DNA content in maize endosperm nuclei revealed progressive increases beyond the triploid level, attributing this to repeated replication cycles without division. Concurrent studies by F. D'Amato and others documented endopolyploidy in various plant tissues, such as root tips and reproductive organs, using Feulgen staining to visualize DNA amplification. These descriptive efforts established endoreduplication as a widespread feature in , particularly for storage and cell enlargement. By the , research shifted from purely cytological descriptions to molecular investigations, driven by the identification of regulators involved in endoreduplication. Seminal studies in , such as those by Lilly and Spradling (1996), linked cyclin E and activity to the endocycle, showing how their oscillation enables repeated S phases without . In , works like Grafi and Larkins (1995) began elucidating similar controls in endosperm, marking the transition to a mechanistic understanding that underscored endoreduplication's role in tissue differentiation and growth.

Mechanisms

Core Process

Endoreduplication is a specialized variant of the cell cycle characterized by repeated rounds of DNA synthesis without intervening mitosis or cytokinesis, resulting in polyploid nuclei. The process begins in the G1 phase, where cells initiate progression to the S phase for DNA replication, doubling the genomic content from 2C to 4C. Following S phase, instead of advancing to a full mitotic (M) phase, cells bypass the G2/M transition, directly re-entering another S phase to form successive endocycles. This modified cycle prevents chromosome segregation and cell division, allowing the accumulation of multiple genome copies within a single nucleus. A key feature of endoreduplication is the circumvention of mitotic entry checkpoints, particularly those governing the activation of cyclin-dependent kinase 1 (CDK1), which is essential for mitotic progression in standard cell cycles. In endoreplicating cells, the absence or inactivation of CDK1 and its mitotic activators—such as cyclin B—prevents nuclear envelope breakdown, chromosome condensation, and spindle assembly, thereby skipping mitosis entirely. This bypass enables the re-licensing of replication origins and repeated DNA synthesis without the risk of erroneous chromosome separation. The nuclear morphology undergoes notable changes, with chromosomes undergoing endoreduplication while remaining unseparated; in certain cell types, this leads to the formation of polytene chromosomes, where multiple chromatids align in register to create thick, banded structures. The duration and number of endocycles vary by organism and cell type, typically ranging from 2 to 10 rounds, which can elevate levels up to 1024C or higher. For instance, in trichomes, cells commonly undergo 4 to 5 rounds of endoreduplication, achieving a final DNA content of 32C to 64C. These cycles occur sequentially over a defined developmental period, with each endocycle roughly mirroring the length of a standard plus abbreviated gap phases.

Molecular Components

Endoreduplication relies on a specialized set of cyclin-dependent kinases (CDKs) that drive repeated S phases while suppressing mitotic progression. Central to this process are S-phase promoting cyclin-CDK complexes, such as cyclin E-CDK2 in animals, which promote entry into S phase by phosphorylating key substrates that initiate DNA synthesis. In contrast, CDK1 activity, typically activated by mitotic cyclins A and B to trigger M phase, is inhibited through downregulation of these cyclins, preventing chromosome segregation and cytokinesis. This selective modulation of CDK activities distinguishes endoreduplication from canonical mitosis, allowing cells to accumulate genomic DNA without division. The oscillation model elucidates how CDK activity fluctuates to sustain endocycles, with high levels of S-phase CDK activity during driving replication and subsequent degradation or inhibition reducing activity to a low state in the extended G phase, licensing origins for the next round. This alternating pattern is regulated by the anaphase-promoting complex/cyclosome (APC/C) and its co-activator Fizzy-related (Fzr/Cdh1), which target mitotic cyclins for ubiquitin-mediated degradation to maintain low mitotic CDK activity, as well as by transcription factors that promote expression of S-phase genes. CDK inhibitors, such as p57Kip2 in mammals or Dacapo in , further ensure precise timing of replication events and prevent unscheduled . Such oscillations are conserved across species, from salivary glands to mammalian trophoblasts, underscoring their role in induction. DNA replication machinery in endoreduplicating cells employs core eukaryotic factors, including the (ORC), which binds replication origins to recruit additional components, and the MCM2-7 complex, loaded via Cdc6 and Cdt1 to unwind DNA strands. DNA polymerases are activated post-licensing without the mitotic barriers that would otherwise inhibit re-replication, enabling multiple rounds while avoiding licensing errors through periodic MCM unloading and reloading. Intriguingly, in certain contexts like endoreplication, ORC1 is dispensable, implying ORC-independent origin activation that still relies on MCM for function. Epigenetic modifications, particularly histone H3 lysine 27 trimethylation (), contribute to by silencing non-essential s and maintaining repressive marks during endoreduplication. In plant endosperm and symbiotic nodule cells, levels adjust dynamically with increases, maintaining repressive marks across replication cycles to support specialized cellular functions without disrupting genome integrity. This mark's persistence helps coordinate endoreduplication with developmental , as seen in tissues undergoing high for nutrient storage or .

Endomitosis

Endomitosis represents a variant of endoreplication in which cells execute DNA replication followed by an aborted mitotic phase, featuring chromosome condensation and partial nuclear envelope disassembly but lacking full chromosome segregation and cytokinesis. This process allows for genome amplification while retaining cellular integrity, distinguishing it from standard mitotic division. Unlike pure endocycling, which skips mitosis entirely, endomitosis incorporates these mitotic elements to achieve polyploidy. The outcomes of endomitosis typically include the production of multinucleate cells or polyploid nuclei formed through subsequent fusion of reformed nuclei, resulting in enlarged, often lobulated nuclei. In mammalian megakaryocytes, for instance, repeated endomitotic cycles driven by thrombopoietin signaling generate highly polyploid cells (up to 64N or higher) with a single giant nucleus, enabling massive platelet production without the need for . This contrasts with the uniform replication in standard endoreduplication, where no mitotic features are observed, highlighting endomitosis as a specialized pathway for tissue-specific polyploidization.

Polytenization

Polytenization represents the structural manifestation of endoreduplication, wherein repeated rounds of without lead to the formation of polytene chromosomes characterized by the precise pairing and alignment of homologous chromosomes into multi-stranded cables. In this process, thousands of identical DNA strands—often reaching 1024 copies in salivary glands or up to 1,000,000-fold amplification in species like Rhynchosciara—remain associated, creating supersized, stable structures that maintain a haploid chromosome number despite the polyploid DNA content. This alignment ensures somatic pairing along the entire length, forming a cable-like organization visible under light . Polytene chromosomes exhibit a distinctive banded pattern, with approximately 5,000 dense bands of alternating with lighter interbands, reflecting varying degrees of condensation. These bands correspond to topologically associating domains (TADs), while puffs—localized decondensations appearing as diffuse swellings—mark sites of active transcription. Prominent examples include Balbiani rings in Chironomus tentans salivary glands, which are massive puffs dedicated to synthesizing large RNAs for secretory proteins. The primary structural advantage of polytenization lies in the amplified gene dosage, enabling extraordinarily high levels of gene expression without requiring cell proliferation. For instance, in the silk glands of Bombyx mori, polytene chromosomes achieve up to 400,000-fold replication of fibroin genes, facilitating the massive production of silk proteins essential for cocoon formation. Similarly, in Drosophila follicle cells, localized amplification of chorion genes supports rapid eggshell protein synthesis during oogenesis. In certain developmental contexts, polytene chromosomes undergo resolution through depolytenization, a process that disassembles the multi-stranded structure. This can occur via the action of condensin II complexes, as observed in Drosophila nurse cells during late oogenesis, allowing DNA strands to segregate or disperse. Such reversibility highlights the dynamic nature of polytene organization in response to cellular needs.

Natural Occurrence

In Plants

Endoreduplication is a widespread process in plants, particularly prominent in angiosperms where it facilitates rapid tissue expansion in specialized cell types. It occurs extensively in vegetative and reproductive structures, contributing to the development of enlarged cells without division. In model species like Arabidopsis thaliana, endoreduplication is observed across multiple organs, highlighting its role in post-embryonic growth. Common sites of endoreduplication include epidermal trichomes, where cells in A. thaliana achieve levels up to 32C, enabling the formation of branched, multicellular hair structures. In the of dark-grown A. thaliana seedlings, endoreduplication drives elongation, with reaching 32C in many cells. The represents another key site, particularly in angiosperms like (Zea mays), where endoreduplication supports nutrient accumulation, resulting in highly polyploid nuclei often exceeding 96C. These tissue-specific occurrences underscore endoreduplication's prevalence in both above- and below-ground plant parts. Endoreduplication typically initiates during post-embryonic developmental phases, such as emergence and organ maturation, aligning with periods of cell expansion rather than proliferation. In A. thaliana leaves, for instance, levels can reach 64C in pavement cells during this growth window. Across angiosperms, it is documented in approximately 90% of species, with serving as a classic example of its integration into seed development. In contrast, gymnosperms exhibit endoreduplication far less frequently, with limited reports such as low-level in Ginkgo biloba tissues up to 64C, indicating it is understudied in this group. Quantitative assessments reveal that a significant proportion of cells in affected tissues, such as Arabidopsis leaf epidermis, undergo endoreduplication, leading to a mosaic of ploidy states that support heterogeneous growth. This process briefly correlates with increased cell size in these contexts, enhancing tissue functionality without delving into broader impacts.

In Animals and Fungi

Endoreduplication in animals is primarily associated with developmental processes that enhance secretory capacity and cell size in specific tissues, rather than widespread growth as seen in plants. In insects like Drosophila melanogaster, it prominently occurs in larval salivary gland cells, where repeated DNA replication without mitosis produces polytene chromosomes reaching up to 1024C ploidy levels. This process begins post-embryogenesis during larval development and supports high transcriptional output for synthesizing enzymes and adhesive proteins essential for pupariation. Similarly, in ovarian nurse cells of Drosophila, endoreduplication drives polyploidization through successive endocycles, peaking in the later stages of oogenesis to provision the oocyte with RNAs and proteins, with ploidy levels escalating beyond 1024C in polytene configurations. In mammals, endoreduplication is rarer and confined to specialized cell types, such as giant cells in the . These cells initiate endoreduplication upon differentiation from stem cells, undergoing multiple S-phase cycles without to achieve levels up to 512C by embryonic day 9.5, forming expansive cells that establish a nutrient-transporting barrier between maternal and fetal tissues. This formation typically aligns with early placental development, highlighting endoreduplication's role in reproductive . Endoreduplication is uncommon in most vertebrates but occurs in specific mammalian tissues and some regenerative contexts in other vertebrates, including hepatocyte polyploidization. In fungi, it manifests as a mechanism for somatic polyploidy, particularly under nutrient stress; for example, in Saccharomyces cerevisiae, endoreduplication enables haploid cells to spontaneously form diploids, conferring adaptive advantages in resource-limited environments like those encountered in industrial fermentations. This process often coincides with stationary phase transitions in yeast cultures, linking it briefly to stress responses that buffer genomic instability.

Biological Significance

Cell Differentiation

Endoreduplication facilitates terminal cell differentiation by increasing the nuclear DNA content through repeated rounds of without , thereby amplifying the copy number of genes critical for specialized functions and enhancing their transcriptional output. This mechanism allows polyploid cells to produce higher levels of mRNA and proteins necessary for differentiation, as the multiple gene copies serve as templates for elevated transcription. In , for instance, cells undergo endoreduplication to form polytene chromosomes, which amplify the expression of salivary glue protein genes (such as Sgs genes), enabling the synthesis of adhesive proteins essential for pupal attachment. In , endoreduplication similarly drives differentiation in epidermal cells, such as pavement cells in leaves, where increased levels promote the expression of genes involved in cell specialization and tissue patterning. ( spp.) fiber cells provide another example, undergoing extensive endoreduplication during development to amplify transcription of synthesis genes, supporting the formation of elongated, single-celled structures vital for . These processes highlight how endoreduplication enables cells to acquire specialized identities by boosting the metabolic output required for their roles. The transition to endoreduplication often marks the irreversible end of the proliferative phase, committing cells to a post-mitotic state focused on differentiation rather than division. This one-way shift is enforced by the downregulation of mitotic regulators, preventing re-entry into the and ensuring stable, specialized cellular functions. Endoreduplication's role in terminal differentiation is conserved across kingdoms, appearing in specialized cell types from (e.g., trichomes and ) to animals (e.g., glands and mammalian trophoblasts) and even fungi, underscoring its fundamental importance in multicellular development. These events are orchestrated by conserved genetic controls, such as cyclin-dependent kinases and transcription factors, that coordinate the switch from to endocycles.

Cell and Organism Size

Endoreduplication, by generating polyploid cells through repeated without , often correlates with substantial increases in cell volume due to expanded cytoplasmic content relative to the . In animals, this is exemplified by the salivary glands of larvae, where cells undergo approximately 10 rounds of endoreplication to achieve a level of 1024C, resulting in cells roughly 1000 times larger than typical G1-phase cells and enabling high secretory capacity. This polyploidy-driven enlargement supports tissue-specific functions while contributing to overall organismal growth in localized contexts. At the organismal level, endoreduplication promotes scaling in plants, particularly through its role in endosperm development, where polyploid cells facilitate nutrient accumulation and storage, leading to larger seeds and fruits. For instance, in tomato (Solanum lycopersicum), higher endoreduplication levels in the pericarp and endosperm correlate with increased fruit weight, as polyploidy enhances cell expansion and nutrient provisioning for seed development. Such mechanisms underlie gigantism in certain plant lineages, where endoreduplication amplifies organ size without proportional increases in cell number. However, this relationship is not universal, as does not invariably result in larger cells; in some cases, endoreduplicated cells maintain compact sizes due to regulatory constraints on expansion or compensatory adjustments in . Experimental evidence from mutants confirms the link: in , the fzr2 mutant, which impairs endoreduplication by disrupting the anaphase-promoting complex, exhibits reduced levels and smaller cells, leading to overall diminished organ size despite increased cell numbers as compensation. These findings underscore endoreduplication's role in physical scaling, distinct from its contributions to cellular specialization.

Oogenesis and Embryonic Development

In , endoreduplication plays a critical role in the development of nurse cells, which support maturation by provisioning essential nutrients and macromolecules. In , the 15 nurse cells within the egg chamber undergo multiple rounds of endoreduplication starting at stage 7, transitioning from mitotic divisions to endocycles that result in nuclei with up to 1024C DNA content. This enables nurse cells to achieve high transcriptional output, synthesizing and transporting vast quantities of RNAs, proteins, and other materials through ring canals to the oocyte, which remains diploid and arrests in . Disruption of endoreduplication in these nurse cells leads to defective nutrient transfer, small oocytes, and sterility, underscoring its necessity for successful egg production. During embryonic development in mammals, endoreduplication is prominent in giant cells (TGCs), which emerge from stem cells around the time of implantation. In , TGC differentiation involves exiting the mitotic cycle and initiating endoreduplication at embryonic day 4.5, leading to polyploid nuclei with DNA contents exceeding 1000C after several rounds. These giant cells secrete hormones and invasins that facilitate uterine attachment and placental formation, forming a protective barrier between maternal and embryonic tissues essential for nutrient exchange and preventing immune rejection. Their large size, partly attributable to , supports the production of high levels of signaling molecules required for implantation success. Ploidy dynamics in embryos feature endoreduplication as a transient process confined to specific lineages, with the embryo proper maintaining diploidy while polyploid cells like TGCs persist in extraembryonic tissues. In mice, endoreduplication in TGCs peaks during mid-gestation but does not propagate to fetal cells, resolving through cell-specific terminal differentiation rather than reversion to lower . This compartmentalization ensures developmental stability, as mutants lacking key endoreduplication regulators like geminin can still form viable despite absent TGC polyploidy. Evolutionarily, endoreduplication in oogenesis and early embryogenesis enhances maternal resource allocation by amplifying gene dosage in supportive cells, a mechanism conserved across insects and mammals to optimize reproductive investment. In Drosophila, polyploid nurse cells maximize maternal provisioning for the nutrient-limited oocyte, mirroring how TGC endoreduplication in rodents bolsters placental support for embryonic growth. This strategy likely evolved to balance the metabolic demands of reproduction, allowing efficient transfer of resources without compromising germline integrity.

Genome Buffering

Endoreduplication generates multiple copies of the within a single nucleus, providing a buffering mechanism that enhances tolerance to mutations and by masking deleterious effects through . In polyploid cells produced via endoreduplication, the presence of duplicated alleles allows recessive loss-of-function mutations to be compensated by functional copies, reducing the phenotypic impact of genetic damage compared to diploid cells. This minimizes the propagation of harmful variants, as the additional genomic material acts as a safeguard against random inactivation. In polyploid contexts, endoreduplication also facilitates dosage compensation by enabling balanced across duplicated chromosomes, including adjustments for imbalances where present. This process ensures that increased DNA content does not lead to stoichiometric disruptions in protein complexes, maintaining cellular through regulated transcription levels that scale appropriately with . For instance, in systems with heteromorphic , polyploidy via endoreduplication can mitigate dosage imbalances by providing equivalent copies, though such mechanisms are more pronounced in animals than in lacking prominent . Evidence from model organisms demonstrates reduced lethality associated with polyploid backgrounds induced by endoreduplication-like processes. In , aneuploid strains exhibit proliferation defects and stress sensitivity in diploid contexts, but increased buffers these effects, with only a small fraction of genetic perturbations causing ploidy-specific lethality, allowing better survival under genomic imbalance. This tolerance arises because normalizes perturbations that would otherwise be catastrophic in lower ploidy states. Over the long term, endoreduplication contributes to hybrid vigor in by amplifying genomic in somatic tissues, enhancing resilience and growth phenotypes in hybrid offspring. In hybrids, elevated endoreduplication levels in leaves correlate with increased cell expansion and organ size, promoting superior biomass accumulation relative to parental lines through buffered . This somatic polyploidization supports adaptive advantages in hybrid backgrounds, facilitating evolutionary success without compromising stability.

Stress Response

Endoreduplication functions as a dynamic adaptive response in subjected to environmental stresses, enabling cells to amplify content through repeated endocycles without , thereby enhancing physiological resilience and recovery. This process is triggered by various abiotic and biotic challenges, resulting in temporary that increases cell size and metabolic output to sustain growth under adverse conditions. Unlike constitutive , stress-induced endoreduplication is often reversible, with levels returning to baseline once the stressor is alleviated, allowing to optimize during recovery. Drought stress prominently induces endoreduplication, as seen in cotton (Gossypium arboreum) where the gene GaTOP6B promotes endocycles in leaves and roots, leading to enlarged cells that improve water retention and overall plant vigor. Wounding, which generates DNA double-strand breaks, elicits endoreduplication in Arabidopsis thaliana leaf and root tip cells by downregulating mitotic cyclins, facilitating rapid tissue repair without proliferation. Under salt stress, endoreduplication in tomato (Solanum lycopersicum) pericarp cells contributes to adaptation by sustaining growth and enhancing metabolic activity despite salinity. Endoreduplication also responds to biotic stresses, such as during phytomyxid infections where it drives host cell enlargement to support pathogen development while potentially aiding defense. These outcomes underscore how stress-induced polyploidy amplifies biosynthetic pathways, providing a metabolic advantage during crises. The reversibility of this polyploidy is evident in post-stress scenarios, where endocycle cessation and partial ploidy reduction occur in recovering tissues, such as drought-stressed mosses reverting after rehydration, ensuring long-term cellular homeostasis without permanent genomic instability. This adaptive strategy also contributes to genome stability by buffering replication errors under duress.

Regulation

Genetic Controls

Endoreduplication is primarily regulated by the (Rb) pathway, where inhibition of Rb family proteins releases transcription factors to drive repeated S-phase entry without intervening mitoses. In both plants and animals, activators, such as E2Fa in , promote the expression of genes required for , including those encoding subunits and replication origins, thereby initiating endocycles upon Rb inactivation. This -dependent mechanism ensures selective activation of replication machinery while suppressing mitotic genes, facilitating polyploidization in differentiating cells. Key s contribute to pathway modulation, with D3 playing a central role in mammals. In megakaryocytes, D3 upregulation in response to growth signals activates cyclin-dependent kinases (CDKs) that partially phosphorylate Rb, promoting release and endoreduplication progression. Overexpression of D3;1 in , however, shifts cells toward by enhancing CDK activity, thereby reducing endoreduplication and increasing levels. In , the absence of mitotic regulators like (a ) blocks CDK1 activation for , allowing unchecked E-CDK2 activity to sustain endocycles. The TOR signaling pathway integrates growth cues to control endoreduplication onset, particularly in nutrient-responsive tissues. Activation of TOR in promotes anabolic processes that support endocycle progression, such as and translation of replication factors, while TOR inhibition reduces and cell size. In , TOR similarly drives endoreduplication in hypocotyls by coordinating nutrient availability with cell expansion. Feedback loops involving auto-regulation of replication genes maintain endocycle oscillations. E2F transcription factors directly activate their own promoters and those of replication licensing factors, creating a that amplifies S-phase during endoreduplication. In , Rb-related proteins (RBR) form a regulatory network with E2F to fine-tune this loop, ensuring balanced progression without re-entering .

Environmental Influences

In plants, hormonal signals such as and play key roles in promoting endoreduplication during development. modulates the transition from mitotic cycles to endocycles by influencing activity, particularly in root and tissues. similarly stimulates the onset of endoreplication in roots by restricting meristem size and activating endocycle entry through regulation of genes. In endosperm, an abrupt increase in levels triggers endoreduplication alongside cellular and storage protein expression. In , the regulates endoreduplication in specific tissues, such as the prothoracic gland and follicle cells. Activation of the receptor is essential for switching from mitotic cycles to endocycles during developmental transitions, coordinating hormone signaling with . In , influences endoreplication independently of its effects in certain cell types, linking hormonal cues to growth control. and together govern endocycle progression in diverse species, including salivary glands and cells. Nutrient sensing pathways, particularly involving the target of rapamycin (TOR) complex, enhance endoreduplication in response to glucose and availability. In and animals, TOR signaling integrates nutrient status to promote and endocycling; for instance, //TOR activation drives endoreplication in tissues under nutrient-rich conditions. Glucose-TOR signaling reprograms transcription to favor endocycles in plant meristems, linking energy abundance to onset. In , TOR assesses larval nutrient levels to synchronize endoreduplication via transcription factors like in ecdysone-producing cells. Light and temperature exert significant influence on endoreduplication, with photoperiod affecting levels in developing plant tissues. In leaves, a shift from short-day to long-day photoperiod induces extensive endoreduplication during floral transition, enhancing nuclear reprogramming. Seedlings of various species, including s, exhibit altered endoreduplication under different light qualities from light-emitting diodes, with blue light promoting higher during . Temperature modulates endoreduplication in floral development; for example, cooler night temperatures (15°C) increase in seedlings compared to warmer conditions, influencing organ growth. Experimental manipulations using chemical inhibitors of cyclin-dependent kinases (CDKs) mimic environmental conditions to induce endoreduplication. CDK blockers like roscovitine arrest cells in G2/M phase in BY-2 suspensions, leading to reversible endoreduplication and cell enlargement upon inhibitor removal. In , inhibitors targeting CDKA;1 and CDKB1;1 complexes, such as those modeled after SIAMESE proteins, promote the switch to endocycles in trichomes and other tissues. These tools demonstrate how reduced CDK activity, analogous to nutrient or hormonal limitations, thresholds cells toward without .

Specialized Cases

Premeiotic Endomitosis in Unisexual Vertebrates

Premeiotic endomitosis serves as a critical reproductive in certain unisexual vertebrates, enabling all-female lineages to produce viable offspring without males. This process is prominently observed in parthenogenetic whiptail lizards of the Aspidoscelis, such as A. tesselata and A. uniparens, which originated from interspecific hybridization and maintain fixed heterozygosity across generations. In these , oogonia undergo endomitosis prior to , effectively doubling the chromosome set to restore pairing capability in a lacking homologous chromosomes from divergent parental . This mechanism contrasts with typical in bisexual vertebrates, where directly reduces from diploid precursors. In some like A. neomexicana, endomitosis occurs infrequently, with diploid oocytes often arresting and only rare polyploid ones proceeding successfully. The process begins with endomitosis in the oogonia, doubling the chromosome number from the diploid somatic level (e.g., 2n ≈ 46 chromosomes in A. tesselata) to a tetraploid state (4n ≈ 92 chromosomes) without . Subsequent elevates the DNA content to 8C. , being identical copies from the duplication, then pair to form 46 bivalents during meiotic I, as evidenced by (FISH) showing colocalized signals on paired chromosomes. Meiosis proceeds through two divisions, incorporating recombination and formation, but yields unreduced diploid eggs (2n ≈ 46 chromosomes) due to the initial doubling. This ensures the eggs retain the full somatic , allowing parthenogenetic embryogenesis upon activation. The outcome of premeiotic endomitosis directly restores diploidy in gametes derived from temporarily polyploid precursors, circumventing the haploid reduction that would otherwise lead to genomic imbalance in hybrid parthenogens. In Aspidoscelis, this results in clonal diploid offspring that inherit the maternal intact, with sister chromatid pairing preserving heterozygosity at loci from the two ancestral genomes. Evolutionarily, this adaptation confers a significant advantage by facilitating stable unisexual in isolated all-female populations, compensating for the lack of genetic input from males and mitigating the fitness costs of hybridization. By enabling consistent production of viable , premeiotic endomitosis supports the persistence of these lineages in diverse habitats, as seen in the comparable of parthenogenetic whiptail to their bisexual relatives. A parallel context exists in the ( formosa), another unisexual that achieves diploid egg production for gynogenetic , though via apomictic suppression of meiotic reduction rather than endomitosis.

Applications in Biotechnology

In biotechnology, endoreduplication has been harnessed to induce in crops, enhancing traits such as fruit size and seedlessness. treatment disrupts formation during , promoting chromosome doubling and endoreduplication-like processes in cells, which results in tetraploid lines used as parental stock for triploid hybrids. For instance, in (Citrullus lanatus), application to diploid seedlings yields tetraploid with approximately double the DNA content, enabling crosses that produce sterile triploid offspring with larger, seedless fruits that dominate commercial production. This approach has similarly improved yield and stress tolerance in other crops like bananas and potatoes by amplifying and cell size through controlled polyploidization. Therapeutically, endoreduplication in supports platelet production to address shortages in . During megakaryopoiesis, thrombopoietin (TPO) drives endomitosis, where cells undergo repeated without , achieving levels up to 64N or higher to expand cytoplasmic volume and synthesize platelet components like cytoskeletal proteins and granules. cultures of megakaryocytes derived from hematopoietic stem cells or induced pluripotent stem cells replicate this process, with TPO supplementation promoting polyploidization and proplatelet formation, yielding functional platelets capable of in animal models. However, current yields remain low (10–400 platelets per megakaryocyte), limiting scalability for clinical use in treating . In , engineering endoreduplication or polyploid states in (Saccharomyces cerevisiae) enables enhanced protein overexpression by increasing gene copy number and metabolic capacity. Targeted mutations or overexpression of regulators like Sch9 stabilize tetraploid strains, which exhibit elevated and secretory protein yields compared to diploids, as seen in optimized strains producing up to 2-fold more enzymes. This polyploid engineering leverages synthetic circuits to mimic endocycles, boosting applications in and pharmaceutical production without compromising viability. A key challenge in these biotechnological applications is maintaining stability to prevent , which arises from meiotic irregularities or genomic imbalances in induced . In crops, nascent tetraploids often suffer chromosome mis-segregation during , leading to aneuploid gametes with reduced and vigor, as observed in and breeding programs. Similarly, in engineered and cultures, unstable triggers imbalances and proteotoxic stress, complicating scalable production. Strategies like for enhanced crossover interference or genetic stabilizers are essential to mitigate these risks and ensure reliable outcomes.

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