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Cleavage (embryo)
Cleavage (embryo)
Cleavage (embryo)
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In embryology, cleavage is the division of cells in the early development of the embryo, following fertilization.[1] The zygotes of many species undergo rapid cell cycles with no significant overall growth, producing a cluster of cells the same size as the original zygote. The different cells derived from cleavage are called blastomeres and form a compact mass called the morula. Cleavage ends with the formation of the blastula, or of the blastocyst in mammals.[2]

Depending mostly on the concentration of yolk in the egg, the cleavage can be holoblastic (total or complete cleavage) or meroblastic (partial or incomplete cleavage). The pole of the egg with the highest concentration of yolk is referred to as the vegetal pole while the opposite is referred to as the animal pole.[2]

Cleavage differs from other forms of cell division in that it increases the number of cells and nuclear mass without increasing the cytoplasmic mass. This means that with each successive subdivision, there is roughly half the cytoplasm in each daughter cell than before that division, and thus twice the ratio of nuclear to cytoplasmic material[3].

Fundamental laws of cleavage

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Cleavage mechanisms and types are governed by four overarching laws. These laws were derived from early embryonic development patterns discovered that guide the classification and study of cleavage:

1) Pfluger's Law states how the spindle formed will elongate in the direction where the resistance is least or minimal.[4]

2) Balfour's Law discovered that cleavage tends to perform at a rate based on the amount of yolk present and the yolk's inverse ratio in holoblastic cleavage. The law also covers how the yolk restricts or interferes with division in the cytoplasm and nucleus.[4]

3) Sack's Law articulates the equal part division of cells during cleavage and describes the two-part division through right angles of the previous planes to make new planes.[4]

4) Hertwig's Law governs the discovery of the nucleus's general location and its spindles in the active protoplasm's center. The law covers every axis of any division's spindle and is generally located at the longest axis of the protoplasmic masses. Like in Sack's law, the discovery of divisions by right angles makes an appearance again, but with the cut of the protoplasmic masses by right angles to their axes.[4]

Mechanism

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The rapid cell cycles are facilitated by maintaining high levels of proteins that control cell cycle progression such as the cyclins and their associated cyclin-dependent kinases (CDKs). The complex cyclin B/CDK1 also known as MPF (maturation promoting factor) promotes entry into mitosis.

The processes of karyokinesis (mitosis) and cytokinesis work together to result in cleavage. The mitotic apparatus is made up of a central spindle and polar asters made up of polymers of tubulin protein called microtubules. The asters are nucleated by centrosomes and the centrosomes are organized by centrioles brought into the egg by the sperm as basal bodies. Cytokinesis is mediated by the contractile ring made up of polymers of actin protein called microfilaments. Karyokinesis and cytokinesis are independent but spatially and temporally coordinated processes. While mitosis can occur in the absence of cytokinesis, cytokinesis requires the mitotic apparatus.

The end of cleavage coincides with the beginning of zygotic transcription. This point in non-mammals is referred to as the midblastula transition and appears to be controlled by the nuclear-cytoplasmic ratio (about 1:6).

Types of cleavage

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Determinate

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Determinate cleavage (also called mosaic cleavage) is in most protostomes. It results in the developmental fate of the cells being set early in the embryo development. Each blastomere produced by early embryonic cleavage does not have the capacity to develop into a complete embryo.[2]

Indeterminate

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A cell can only be indeterminate (also called regulative) if it has a complete set of undisturbed animal/vegetal cytoarchitectural features. It is characteristic of deuterostomes—when the original cell in a deuterostome embryo divides, the two resulting cells can be separated, and each one can individually develop into a whole organism.[2]

Holoblastic

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In holoblastic cleavage, the zygote and blastomeres are completely divided during the cleavage, so the number of blastomeres doubles with each cleavage. In the absence of a large concentration of yolk, four major cleavage types can be observed in isolecithal cells (cells with a small, even distribution of yolk) or in mesolecithal cells or microlecithal cells (moderate concentration of yolk in a gradient)—bilateral holoblastic, radial holoblastic, rotational holoblastic, and spiral holoblastic, cleavage.[5] These holoblastic cleavage planes pass all the way through isolecithal zygotes during the process of cytokinesis. Coeloblastula is the next stage of development for eggs that undergo these radial cleavages. In holoblastic eggs, the first cleavage always occurs along the vegetal-animal axis of the egg, the second cleavage is perpendicular to the first. From here, the spatial arrangement of blastomeres can follow various patterns, due to different planes of cleavage, in various organisms.

Bilateral

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The first cleavage results in bisection of the zygote into left and right halves. The following cleavage planes are centered on this axis and result in the two halves being mirror images of one another. In bilateral holoblastic cleavage, the divisions of the blastomeres are complete and separate; compared with bilateral meroblastic cleavage, in which the blastomeres stay partially connected.[2]

Radial

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Radial cleavage is characteristic of the deuterostomes, which include some vertebrates and echinoderms, in which the spindle axes are parallel or at right angles to the polar axis of the oocyte.[2]

Rotational

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Rotational cleavage involves a normal first division along the meridional axis, giving rise to two daughter cells. The way in which this cleavage differs is that one of the daughter cells divides meridionally, whilst the other divides equatorially.[2]

The nematode C. elegans, a popular developmental model organism, undergoes holoblastic rotational cell cleavage.[6]

Spiral

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Spiral cleavage is conserved between many members of the lophotrochozoan taxa, referred to as Spiralia.[7] Most spiralians undergo equal spiral cleavage, although some undergo unequal cleavage (see below).[8] This group includes annelids, molluscs, and sipuncula. Spiral cleavage can vary between species, but generally the first two cell divisions result in four macromeres, also called blastomeres, (A, B, C, D) each representing one quadrant of the embryo. These first two cleavages are not oriented in planes that occur at right angles parallel to the animal-vegetal axis of the zygote.[7] At the 4-cell stage, the A and C macromeres meet at the animal pole, creating the animal cross-furrow, while the B and D macromeres meet at the vegetal pole, creating the vegetal cross-furrow.[9] With each successive cleavage cycle, the macromeres give rise to quartets of smaller micromeres at the animal pole.[10][11] The divisions that produce these quartets occur at an oblique angle, an angle that is not a multiple of 90 degrees, to the animal-vegetal axis.[11] Each quartet of micromeres is rotated relative to their parent macromere, and the chirality of this rotation differs between odd- and even-numbered quartets, meaning that there is alternating symmetry between the odd and even quartets.[7] In other words, the orientation of divisions that produces each quartet alternates between being clockwise and counterclockwise with respect to the animal pole.[11] The alternating cleavage pattern that occurs as the quartets are generated produces quartets of micromeres that reside in the cleavage furrows of the four macromeres.[9] When viewed from the animal pole, this arrangement of cells displays a spiral pattern.

D quadrant specification through equal and unequal cleavage mechanisms. At the 4-cell stage of equal cleavage, the D macromere has not been specified yet. It will be specified after the formation of the third quartet of micromeres. Unequal cleavage occurs in two ways: asymmetric positioning of the mitotic spindle, or through the formation of a polar lobe (PL).

Specification of the D macromere and is an important aspect of spiralian development. Although the primary axis, animal-vegetal, is determined during oogenesis, the secondary axis, dorsal-ventral, is determined by the specification of the D quadrant.[11] The D macromere facilitates cell divisions that differ from those produced by the other three macromeres. Cells of the D quadrant give rise to dorsal and posterior structures of the spiralian.[11] Two known mechanisms exist to specify the D quadrant. These mechanisms include equal cleavage and unequal cleavage.

In equal cleavage, the first two cell divisions produce four macromeres that are indistinguishable from one another. Each macromere has the potential of becoming the D macromere.[10] After the formation of the third quartet, one of the macromeres initiates maximum contact with the overlying micromeres in the animal pole of the embryo.[10][11] This contact is required to distinguish one macromere as the official D quadrant blastomere. In equally cleaving spiral embryos, the D quadrant is not specified until after the formation of the third quartet, when contact with the micromeres dictates one cell to become the future D blastomere. Once specified, the D blastomere signals to surrounding micromeres to lay out their cell fates.[11]

In unequal cleavage, the first two cell divisions are unequal producing four cells in which one cell is bigger than the other three. This larger cell is specified as the D macromere.[10][11] Unlike equally cleaving spiralians, the D macromere is specified at the four-cell stage during unequal cleavage. Unequal cleavage can occur in two ways. One method involves asymmetric positioning of the cleavage spindle.[11] This occurs when the aster at one pole attaches to the cell membrane, causing it to be much smaller than the aster at the other pole.[10] This results in an unequal cytokinesis, in which both macromeres inherit part of the animal region of the egg, but only the bigger macromere inherits the vegetal region.[10] The second mechanism of unequal cleavage involves the production of an enucleate, membrane bound, cytoplasmic protrusion, called a polar lobe.[10] This polar lobe forms at the vegetal pole during cleavage, and then gets shunted to the D blastomere.[9][10] The polar lobe contains vegetal cytoplasm, which becomes inherited by the future D macromere.[11]

Spiral cleavage in marine snail of the genus Trochus

Meroblastic

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In the presence of a large concentration of yolk in the fertilized egg cell, the cell can undergo partial, or meroblastic, cleavage. Two major types of meroblastic cleavage are discoidal and superficial.[2]

  • Discoidal
In discoidal cleavage, the cleavage furrows do not penetrate the yolk. The embryo forms a disc of cells, called a blasto-disc, on top of the yolk. Discoidal cleavage is commonly found in monotremes, birds, reptiles, and fish that have telolecithal egg cells (egg cells with the yolk concentrated at one end).[2] The layer of cells that have incompletely divided and are in contact with the yolk are called the "syncytial layer".
  • Superficial
In superficial cleavage, mitosis occurs but not cytokinesis, resulting in a polynuclear cell. With the yolk positioned in the center of the egg cell, the nuclei migrate to the periphery of the egg, and the plasma membrane grows inward, partitioning the nuclei into individual cells. Superficial cleavage occurs in arthropods that have centrolecithal egg cells (egg cells with the yolk located in the center of the cell). This type of cleavage can work to promote synchronicity in developmental timing, such as in Drosophila.[12]
Summary of the main patterns of cleavage and yolk accumulation (after [2],[13], and [14]).
I. Holoblastic (complete) cleavage II. Meroblastic (incomplete) cleavage

A. Isolecithal (sparse, evenly distributed yolk)

B. Mesolecithal (moderate vegetal yolk disposition)

A. Telolecithal (dense yolk throughout most of cell)

B. Centrolecithal (yolk in center of egg)

  • Superficial cleavage (most insects)

Mammals

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"Morula" redirects here. For other uses, see Morula (disambiguation).
First stages of cleavage in a fertilized mammalian egg. Semidiagrammatic. z.p. Zona pellucida. p.gl. Polar bodies a. Two-cell stage b. Four-cell stage c. Eight-cell stage d, e. Morula stage

Compared to other fast developing animals, mammals have a slower rate of division that is between 12 and 24 hours. Initially synchronous, these cellular divisions progressively become more and more asynchronous. Zygotic transcription starts at the two-, four-, or eight-cell stage depending on the species (for example, mouse zygotic transcription begins towards the end of the zygote stage and becomes significant at the two-cell stage, whereas human embryos begin zygotic transcription at the eight-cell stage). Cleavage is holoblastic and rotational.

In human embryonic development at the eight-cell stage, having undergone three cleavages the embryo starts to change shape as it develops into a morula and then a blastocyst. At the eight-cell stage the blastomeres are initially round, and only loosely adhered. With further division in the process of compaction the cells flatten onto one another.[15] At the 16–cell stage the compacted embryo is called a morula.[16][17] Once the embryo has divided into 16 cells, it begins to resemble a mulberry, hence the name morula (Latin, morus: mulberry).[18] Concomitantly, they develop an inside-out polarity that provides distinct characteristics and functions to their cell-cell and cell-medium interfaces.[19][20] As surface cells become epithelial, they begin to tightly adhere as gap junctions are formed, and tight junctions are developed with the other blastomeres.[21][16] With further compaction the individual outer blastomeres, the trophoblasts, become indistinguishable as they become organised into a thin sheet of tightly adhered epithelial cells. They are still enclosed within the zona pellucida. The morula is now watertight, to contain the fluid that the cells will later pump into the embryo to transform it into the blastocyst.

In humans, the morula enters the uterus after three or four days, and begins to take in fluid, as sodium-potassium pumps on the trophoblasts pump sodium into the morula, drawing in water by osmosis from the maternal environment to become blastocoelic fluid. As a consequence to increased osmotic pressure, the accumulation of fluid raises the hydrostatic pressure inside the embryo.[22] Hydrostatic pressure breaks open cell-cell contacts within the embryo by hydraulic fracturing.[23] Initially dispersed in hundreds of water pockets throughout the embryo, the fluid collects into a single large cavity, called blastocoel, following a process akin to Ostwald ripening.[23] Embryoblast cells also known as the inner cell mass form a compact mass of cells at the embryonic pole on one side of the cavity that will go on to produce the embryo proper. The embryo is now termed a blastocyst.[16][24] The trophoblasts will eventually give rise to the embryonic contribution to the placenta called the chorion.

A single cell can be removed from a pre-compaction eight-cell embryo and used for genetic screening, and the embryo will recover.[25][26]

Differences exist between cleavage in placental mammals and other mammals.

References

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Further reading

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Cleavage (embryo)

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Cleavage in embryology refers to the initial series of rapid, successive mitotic cell divisions that transform the single-celled zygote into a multicellular structure known as the blastula, without a concomitant increase in the overall size or mass of the embryo. These divisions produce smaller daughter cells called blastomeres, which partition the zygotic cytoplasm while maintaining the cytoplasmic volume through the absence of growth phases (G1 and G2) in the cell cycle. In most animals, cleavage is driven by maternal factors such as stored mRNAs and proteins in the egg. In animals with external development, such as many amphibians and invertebrates, the process often concludes at the mid-blastula transition, when zygotic genome activation begins; in mammals, zygotic genome activation occurs earlier during cleavage stages. The pattern of cleavage varies significantly across species, primarily influenced by the amount and distribution of yolk in the egg, resulting in two main types: holoblastic (complete) cleavage, where the entire egg divides evenly, and meroblastic (partial) cleavage, where division is restricted to the active cytoplasmic region, leaving the yolk mass undivided. Holoblastic cleavage is typical in species with yolk-poor eggs, such as mammals (e.g., rotational cleavage in mice, leading to a morula and then blastocyst) and amphibians (e.g., radial cleavage in frogs like Xenopus). In contrast, meroblastic cleavage occurs in yolk-rich eggs of teleost fish (e.g., discoidal in zebrafish), birds (e.g., superficial in chickens), and reptiles, where divisions form a blastodisc atop the yolk. This stage is crucial for embryonic development as it establishes the basic cellular architecture, balances the nucleus-to-cytoplasm ratio, and sets the stage for subsequent processes like , where cell layers differentiate into germ layers. In mammals, cleavage culminates in the formation of a , featuring an (future proper) and an outer layer (for implantation). Disruptions in cleavage can lead to developmental abnormalities, underscoring its foundational role in multicellular organization.

Introduction to Cleavage

Definition and Process

Cleavage in refers to the series of rapid mitotic divisions that occur in the immediately following fertilization, resulting in the production of smaller daughter cells known as blastomeres without accompanying significant or increase in overall embryonic . These divisions are driven by maternal factors in the egg, such as stored mRNAs and proteins, and occur without growth phases (G1 and G2) in the , maintaining the overall embryonic volume. This process partitions the original zygotic into progressively smaller compartments, converting the single-celled into a multicellular structure while conserving the total cytoplasmic content. The cleavage process typically begins with the first division of the into two blastomeres at the 2-cell stage, followed by subsequent mitotic divisions that yield the 4-cell, 8-cell, and higher stages. In many , particularly mammals, this leads to the formation of a compact ball of cells known as the morula, typically at the 16- to 32-cell stage, before progressing to the blastula. Each division halves the size of the blastomeres relative to their predecessors, emphasizing the role of cleavage in increasing cell number rather than mass, which facilitates the transition to later developmental stages such as blastula formation. Key terms in this process include the , the fertilized that initiates cleavage; blastomeres, the resulting totipotent or pluripotent cells produced by these divisions; and the morula, the mulberry-like cluster representing the culmination of early cleavage before fluid accumulation leads to further reorganization. Through these divisions, the zygote's is equitably or unequally distributed among blastomeres, laying the groundwork for embryonic differentiation. The phenomenon of cleavage was first systematically observed in the , with early descriptions of the process in embryos recorded by Prevost and Dumas in 1824, and later advanced through histological studies by such as Wilhelm His, who in 1868 pioneered the use of serial sectioning techniques in studying chick embryo development.

Biological Significance

Cleavage plays a pivotal role in embryonic development by transforming the large, single-celled into a multicellular blastula through successive mitotic divisions without significant , thereby partitioning the cytoplasmic volume into numerous smaller blastomeres that establish the foundation for subsequent stages such as and . This process creates a hollow ball of cells, the blastula, which provides the structural framework for the inward migration and reorganization of cells during to form the three primary germ layers—, , and —essential for tissue and organ differentiation. The biological importance of cleavage extends to the spatial allocation of cytoplasmic determinants, which are maternally inherited factors that influence cell fate decisions, as well as the breaking of embryonic and the initial establishment of body axes, such as anterior-posterior and dorsal-ventral orientations. These early divisions position blastomeres in specific locations relative to distribution and regulatory molecules, thereby initiating the regulative or developmental programs that determine whether cell fates are fixed (determinate cleavage) or flexible (indeterminate cleavage). Cleavage patterns exhibit remarkable evolutionary conservation across metazoans, serving as an ancestral mechanism adapted to diverse developmental strategies, such as direct development in vertebrates versus indirect development with larval stages in many , where variations like holoblastic or meroblastic divisions correlate with content and environmental demands. Disruptions in cleavage, including abnormal division timings or patterns, often result in embryonic arrest, , or mosaicism, leading to developmental defects or , as seen in embryos where 50–70% fail to reach the stage due to such errors; for instance, polyspermy-induced abnormalities can trigger faulty cleavage and subsequent demise.

Principles of Cleavage

Fundamental Laws

The fundamental laws of cleavage describe the observational principles that govern the initial mitotic divisions of the in early embryogenesis, ensuring the progressive partitioning of the into blastomeres while maintaining the embryo's overall volume. These laws emerged from microscopic studies of diverse species in the late , primarily by European zoologists who examined transparent eggs such as those of sea urchins, frogs, and nematodes. Pioneering work by figures like Oscar Hertwig, who observed spindle behavior in echinoderms, and Edouard van Beneden, who detailed nuclear dynamics in parasitic worms, laid the groundwork for understanding cleavage as a regulated, non-growth process distinct from later somatic divisions. Although these laws apply broadly to holoblastic cleavage in yolk-poor eggs, they often show exceptions in highly yolky oocytes, where uneven yolk distribution impedes equal partitioning or complete , leading to meroblastic patterns._9) A core principle is the of equal division, encapsulated in Sach's laws proposed in , which posits that blastomeres typically divide the equally during early cleavage stages in many , producing daughter cells of comparable . This equitable partitioning, observed in oligolecithal eggs like those of amphibians and echinoderms, prevents volume increase and facilitates uniform distribution of maternal factors. Each successive division plane also tends to intersect the previous one at right angles, promoting symmetrical arrangements. However, in telolecithal eggs with concentrated at the vegetal pole, this law is violated, resulting in smaller animal-pole blastomeres and larger yolk-laden ones. Another key tenet addresses the synchrony between nuclear and cytoplasmic division: in standard cleavage, proceeds in with karyokinesis, ensuring complete cellular separation after each nuclear division, as opposed to syncytial modes in some arthropods where nuclei multiply rapidly within a shared before enveloping membranes form. Early microscopists like Édouard Balbiani, studying oogenesis and superficial cleavage in the 1870s, noted cases of asynchronous division in yolky eggs, but in typical cleavage, this coordination prevails to generate discrete blastomeres from the outset. Van Beneden's analyses of cleavage further illustrated how such synchrony supports mosaic development in . The orientation of cleavage planes is dictated by what is known as Hertwig's rule (or law), established in , which states that the mitotic spindle aligns along the cell's longest axis, yielding meridional planes (parallel to the animal-vegetal axis) or equatorial planes (perpendicular to it) based on spindle positioning in the active . This principle, derived from Hertwig's observations of and embryos, ensures divisions follow the egg's inherent polarity and shape constraints, with the spindle typically forming in regions of least resistance away from . In yolky eggs, spindle misalignment can produce oblique or partial planes, deviating from this rule.

Mechanisms of Cell Division

Cleavage divisions in early embryos are characterized by rapid mitotic cycles that prioritize and segregation over cellular growth. These cycles typically consist of alternating S () and M () phases, with G1 and G2 gap phases largely absent or dramatically shortened to enable divisions every 10-30 minutes in species like mice and . This streamlined progression contrasts with cycles and adheres to the fundamental laws of cleavage by ensuring equitable cytoplasmic partitioning without net increase in blastomere volume. The speed of these divisions is regulated by cyclin-dependent kinases (CDKs), particularly CDK1 and CDK2, which form complexes with maternal to drive phase transitions. Maternal factors, including stored mRNAs and proteins inherited from the , activate these CDKs to bypass checkpoint controls and sustain rapid oscillations between S and M phases. For instance, in embryos, maternal Cdk2- E complexes initiate early cleavages lacking G1 phases, while in , the subcortical maternal complex stabilizes CDC25B via 14-3-3 proteins to promote CDK1 activation and timely mitotic entry. Similarly, A2-CDK2 activity in one-cell embryos supports the initial divisions by phosphorylating key regulators before zygotic transcription. Cytokinesis during cleavage relies on the formation of an actomyosin contractile ring at the cell equator, which constricts to separate daughter cells. Astral microtubules emanating from the spindle poles interact with the cortex to position and stabilize this ring, ensuring precise furrow ingression. In C. elegans embryos, astral microtubules exhibit biphasic activity: initial promotion of ring assembly in early , followed by suppression of polar contraction in late to refine furrow placement. These microtubule-cortex signals are conserved across animals, guiding divisions in the absence of growth. Energy for cleavage derives exclusively from maternal stores, such as oocyte-derived mRNAs, proteins, and nutrients, as zygotic transcription is minimal and no net cellular growth occurs—each division halves blastomere volume without compensatory expansion. abundance influences division dynamics; in meroblastic cleavage, as seen in eggs with high content (e.g., birds and reptiles), divisions are confined to a superficial disc and proceed more slowly due to 's impedance of cytoplasmic mixing and furrow progression compared to holoblastic patterns in low- eggs. This reliance on maternal resources limits division rates and enforces the cleavage laws of equitable partitioning.

Classification of Cleavage Types

Determinate Cleavage

Determinate cleavage, also known as cleavage, is a pattern of embryonic in which the fate of each blastomere is specified early during development through the unequal distribution of cytoplasmic determinants, such as mRNAs and proteins, within the cytoplasm. These determinants are segregated into specific blastomeres during cleavage, committing them autonomously to particular developmental paths without reliance on interactions with neighboring cells. This process results in a -like embryo, where each cell differentiates into its predetermined tissue or organ type, akin to tiles in a mosaic forming a fixed image. Key characteristics of determinate cleavage include unequal cell divisions that produce blastomeres of varying sizes and potencies, often leading to a lack of regulative capacity in the . If a blastomere is removed or destroyed early in development, the fails to compensate, resulting in the absence of the corresponding cell types or structures, as the remaining cells cannot adjust their fates to fill the gap. This contrasts sharply with regulative development, where embryos exhibit flexibility and can reorganize to produce a complete even after perturbations. In determinate cleavage, development proceeds directly toward a fixed , bypassing stages of totipotency seen in more flexible systems. A classic example of determinate cleavage occurs in the nematode , where the zygote undergoes rotational holoblastic cleavage with highly invariant cell lineages. The first asymmetrical division segregates cytoplasmic determinants like P-granules to the posterior, specifying germ cell fate, while anterior cells receive factors such as SKN-1 for pharyngeal development. Each blastomere's progeny follow predetermined paths, yielding exactly 558 somatic cells in the newly hatched larva, with no compensatory regulation if cells are ablated. Similar patterns are observed in protostome invertebrates, including annelids, where blastomeres autonomously form specific segments; mollusks, such as the limpet , in which trochoblast cells differentiate into ciliary bands without external cues; and tunicates, where isolating the 8-cell stage blastomeres results in each producing only its destined larval tissues, like muscle from the B4.1 cell. These examples illustrate direct development without totipotent phases, emphasizing the role of localized determinants in fate commitment. Determinate cleavage is evolutionarily linked to protostome developmental strategies, where early fate restriction supports efficient, stereotyped body plans in diverse , differing from the regulative modes prevalent in deuterostomes. It is often associated with spiral cleavage patterns, though the focus here remains on the deterministic fate assignment rather than geometry.

Indeterminate Cleavage

Indeterminate cleavage refers to a pattern of early embryonic cell division in which the blastomeres are initially equivalent and totipotent, meaning each can potentially develop into a complete organism if isolated, with cell fates determined later through interactions rather than being fixed from the outset. This contrasts with more rigid developmental programs and is a hallmark of regulative development, where the embryo exhibits flexibility in response to environmental cues or perturbations. Key characteristics include the high regulative potential of the early , allowing it to compensate for cell loss or damage by reorganizing development to produce a viable individual. For instance, classic experiments by in the late demonstrated that separating the first two blastomeres of embryos results in two complete larvae, underscoring the totipotency and compensatory capacity inherent to this cleavage type. This regulative ability is prevalent in deuterostomes and enables indirect development, where larval stages precede adult forms, facilitating evolutionary adaptability. Examples of indeterminate cleavage are found across various deuterostome taxa, including echinoderms like sea urchins (Strongylocentrotus purpuratus), where radial holoblastic divisions produce a blastula capable of full regulation; amphibians such as frogs (Xenopus laevis), exhibiting unequal holoblastic cleavage with totipotent early cells; and mammals, where rotational cleavage in species like mice leads to a blastocyst with pluripotent inner cell mass cells that support twinning. These cases illustrate how indeterminate cleavage supports robust embryogenesis in diverse environments. At the molecular level, indeterminate cleavage involves an initial uniform distribution of cytoplasmic determinants in the , avoiding early localization that would commit to specific lineages. Cell fates are subsequently specified through conditional mechanisms, including cell-cell interactions and inductive signals that establish gradients; for example, in amphibians, the activin diffuses from the vegetal pole to induce mesodermal fates in overlying cells based on concentration thresholds, promoting regulative adjustments. This reliance on dynamic signaling pathways, such as those involving TGF-β family members, ensures flexibility in development.

Holoblastic Cleavage

Holoblastic cleavage refers to the complete division of the zygote's into a series of smaller cells known as blastomeres, where the cleavage furrows extend through the entire without leaving an uncleaved mass. This process results in the total cellularization of the , with platelets either absent or evenly distributed among the daughter cells, enabling uniform partitioning of the cytoplasmic contents. The primary influencing factor for holoblastic cleavage is the low yolk content in the egg, characteristic of microlecithal (minimal yolk, as in mammals) or mesolecithal (moderate yolk, as in amphibians) ova, which does not impede the full progression of cleavage planes. For instance, in echinoderms such as sea urchins, the absence of substantial yolk allows for equal and synchronous divisions, while in mammals, the sparse yolk distribution supports rotational cleavage despite the slower division rate. In contrast to eggs with high yolk concentrations, which restrict cleavage to partial divisions, low-yolk eggs facilitate this holistic process, often leading to blastomeres of comparable size in early stages. The general outcome of holoblastic cleavage is the formation of a hollow, spherical structure called the blastula, featuring a central fluid-filled cavity known as the , which arises from the separation of blastomeres and provides structural support for subsequent . This complete division contrasts sharply with partial cleavages, where an undivided mass persists, altering embryonic architecture and development. Holoblastic cleavage is evolutionarily prevalent in many , such as echinoderms and annelids, and in certain vertebrates including amphibians and mammals, reflecting an ancestral pattern adapted to yolk-poor reproductive strategies that prioritize rapid, equitable . This type of cleavage manifests in various patterns, such as radial or spiral arrangements of blastomeres, which are explored in detail elsewhere.

Meroblastic Cleavage

Meroblastic cleavage is characterized by the partial division of the , in which cell divisions occur only in a restricted portion of the , typically the animal pole, while the vegetal region remains undivided. This incomplete arises primarily due to the high concentration of , a nutrient-rich material that impedes the formation of cleavage furrows across the entire . In eggs with telolecithal distribution—where is asymmetrically concentrated at the vegetal pole—the physical and biochemical properties of the limit spindle apparatus extension and furrow ingression, confining divisions to the cytoplasm-rich animal hemisphere. Such cleavage is prevalent in -abundant eggs of oviparous vertebrates, including teleost fishes, reptiles, and birds. The primary outcome of meroblastic cleavage is the formation of a blastodisc, a flattened disc or cap of blastomeres that proliferates atop the intact mass, rather than a fully spherical blastula. This structure ensures that the develops as a superficial layer nourished by the underlying , which serves as a nutritive reservoir without being partitioned into cells. In fishes like , for instance, the blastodisc starts as a of approximately 8 by 4 cells at the 32-cell stage, transitioning to a multilayered array by later stages, while the yolk cell remains syncytial and non-contributory to the proper. This partial division supports efficient in large eggs, preventing mechanical disruption of the and promoting rapid early development. From an evolutionary perspective, meroblastic cleavage has evolved independently at least five times among craniates, reflecting adaptations to yolk-rich ova in lineages transitioning to and terrestrial environments. Ancestrally, eggs likely underwent holoblastic cleavage similar to that in basal chordates and amphibians, but the accumulation of substantial in advanced groups—such as teleosts, sauropsids, and some chondrichthyans—favored partial cleavage to optimize nutrient storage and embryonic viability in externally laid eggs. This pattern underscores driven by selective pressures for larger, self-sustaining eggs, with subtypes like discoidal cleavage representing specialized forms in birds and .

Patterns of Holoblastic Cleavage

Radial Cleavage

Radial cleavage is a pattern of holoblastic cleavage characterized by the symmetric alignment of blastomeres in vertical tiers directly above one another, maintaining radial around the animal-vegetal axis of the embryo. This arrangement results from cleavage planes that are either meridional (passing through the poles) or equatorial (perpendicular to the axis), producing a stacked, cylindrical structure rather than offset or twisted cells. The pattern is prevalent in animals exhibiting indeterminate development, such as echinoderms like sea urchins and vertebrates like amphibians, where early blastomeres retain developmental flexibility. In these organisms, the radial configuration ensures that daughter cells remain equivalently positioned relative to maternal cytoplasmic factors, contrasting with more asymmetric cleavage types. The process begins with the first cleavage division, which is meridional and bisects the into two equal blastomeres along the animal-vegetal axis. The second division is also meridional but oriented to the first, yielding four equal blastomeres arranged in a single tier around the axis. The third division occurs equatorially, splitting the into two tiers of four cells each—known as the quartet stage—with the upper tier (animal) consisting of smaller micromeres and the lower (vegetal) of larger macromeres in sea urchins; in amphibians, this equatorial plane is shifted toward the animal pole due to concentration, resulting in unequal cell sizes. Subsequent divisions continue this radial progression, forming a morula and then a blastula with a central cavity. This cleavage pattern holds biological significance by promoting the even distribution of cytoplasmic determinants along the animal-vegetal axis, which guides axial patterning and specification during later stages like . Additionally, the regulative potential is high, as individual blastomeres separated early can each develop into a complete or , reflecting the indeterminate of the development.

Spiral Cleavage

Spiral cleavage is a pattern of holoblastic embryonic observed in certain protostomes, particularly within the , where the third cleavage plane is oblique to the first two vertical planes, resulting in a rotational displacement of the upper quartet of blastomeres relative to the lower quartet, either (dextral) or counterclockwise (sinistral). This oblique orientation, typically at a 45° angle to the animal-vegetal axis, produces a characteristic spiral arrangement of daughter cells, distinguishing it from radial symmetry. The process begins with the first two cleavages in meridional (vertical) planes at right angles to each other, forming four equal blastomeres aligned along the animal-vegetal axis. The third cleavage is equatorial but oblique, causing the animal quartet to twist, which establishes chirality and leads to the formation of distinct cell types: smaller micromeres at the animal pole and larger macromeres at the vegetal pole during subsequent divisions. These divisions continue in a stereotyped manner, generating four embryonic quadrants labeled A, B, C, and D, with corresponding micromeres (1a–1d, 2a–2d, etc.) and macromeres (1A–1D, etc.), where the numbering reflects the sequence of divisions. In protostomes such as mollusks and annelids, this pattern is often equal in early stages but becomes unequal as micromeres form, and it is typically determinate, meaning cell fates are fixed early based on position. This cleavage pattern holds significance in establishing bilateral asymmetry and the spiralian , where early cell arrangements prefigure organ formation and segment patterning in descendants like mollusks (e.g., snails and clams) and annelids (e.g., earthworms). By introducing from the eight-cell stage onward, it supports a mosaic-like development with restricted cell potencies, facilitating evolutionary conservation across diverse phyla and serving as a key trait in phylogenetic studies of protostomes.

Bilateral Cleavage

Bilateral cleavage is a variant of holoblastic cleavage in which the division planes of the early embryonic cells are oriented to produce mirror-image halves, establishing bilateral symmetry along a single primary axis from the outset of development. This pattern results in a symmetrical arrangement of blastomeres that reflects the future left-right organization of the , distinguishing it as an intermediate form between the fully of radial cleavage and the rotational of spiral cleavage. It typically occurs in eggs with moderate distribution, such as isolecithal or mesolecithal types, allowing complete division of the without yolk interference. The process begins with the first cleavage, which is meridional and bisects the precisely into left and right halves, aligning with the animal-vegetal axis to immediately impose bilateral . The second cleavage is also meridional but oriented to the first, producing four equal blastomeres, while the third cleavage is equatorial, further subdividing cells while preserving the mirrored layout. Subsequent divisions maintain this symmetry through aligned mitotic spindles and cleavage furrows, often resulting in a small by the 32-cell stage; in many cases, these early divisions are determinate, meaning the blastomeres have fixed developmental fates. This cleavage pattern is prominently observed in , such as ascidians like Styela partita, where the bilateral divisions partition key cytoplasmic determinants (e.g., the yellow crescent region for induction) equally between sides, ensuring symmetric cell lineages. The significance of bilateral cleavage lies in its role in prefiguring the organism's bilateral , facilitating the early specification of dorsal-ventral and left-right axes that guide organ placement and tissue differentiation. By imposing through precise cleavage orientation, it enables the segregation of maternal factors critical for axis formation, supporting subsequent morphogenetic events like and development in bilaterian animals.

Rotational Cleavage

Rotational cleavage is a distinctive pattern of holoblastic observed exclusively in eutherian mammals, characterized by the first division being meridional and equal, dividing the into two identical blastomeres along the animal-vegetal axis. The subsequent second and third divisions are latitudinal (equatorial) and unequal, with one blastomere typically dividing meridionally while the other divides equatorially during the second cleavage, resulting in a rotational reorientation of the daughter cells relative to each other. This asymmetry becomes more pronounced in the third cleavage, where blastomeres produce unequal daughter cells, including smaller inner cells and larger outer cells, contributing to the establishment of . Among holoblastic cleavage types, rotational cleavage proceeds at the slowest rate, with interdivision intervals of 12–24 hours, reflecting adaptations to the mammalian reproductive environment where embryos develop within the before implantation. It is prominently featured in such as mice and humans, where the asynchronous divisions allow for progressive cytoplasmic redistribution without significant influence. The rotational movement of blastomeres during these early divisions facilitates the formation of a compacted morula by the 8- to 16-cell stage, where cells adhere tightly via cell-cell junctions, preparing the embryo for further development. This cleavage pattern holds particular significance in the context of , enabling eutherian mammals to generate a structure suited for uterine implantation and placental nourishment despite the absence of substantial reserves. By promoting unequal cell divisions and rotational , it helps establish embryonic polarity and diverse cell lineages early on, ensuring robust developmental competence in a yolk-independent manner. Detailed aspects of this process in mammalian embryos are explored further in the section on Cleavage in Mammalian Embryos.

Cleavage in Mammalian Embryos

General Features

Mammalian eggs are relatively large cells, measuring approximately 100 μm in diameter in humans, and are characterized by low yolk content compared to those of other vertebrates, though they are enclosed by a protective glycoprotein layer known as the zona pellucida. Cleavage in mammals initiates shortly after fertilization, which typically occurs in the ampulla of the oviduct, where the zygote undergoes its first mitotic divisions while being transported toward the uterus. This process follows a rotational cleavage pattern, distinguishing it from other vertebrate types. The timing of cleavage divisions in mammals is notably slower than in many non-mammalian species, with each cycle taking 12–24 hours in humans. By day 3 post-fertilization, the embryo reaches the 8-cell stage, progressing to a 16–32 cell morula by day 4, forming a compact ball of blastomeres without significant increase in overall size. Early embryonic development relies heavily on maternal transcripts and proteins stored in the , as the embryonic remains largely transcriptionally silent until activation occurs around the 4–8 cell stage. A distinctive feature of mammalian cleavage is the absence of a true during the initial stages; the morula consists of tightly adherent cells lacking a fluid-filled cavity until later . This compact organization supports the embryo's journey through the reproductive tract. Cleavage patterns are largely consistent across eutherian mammals, but marsupials exhibit slight differences, such as variations in the timing and nature of early cell compaction.

Transition to Blastocyst

In mammalian embryos, cleavage divisions culminate in compaction, a critical morphogenetic event occurring at the 8- to 16-cell stage, where blastomeres flatten against each other to form a more spherical structure with increased cell-cell contacts. This process is primarily mediated by E-cadherin, a calcium-dependent adhesion molecule that accumulates and clusters at cell contact sites, reorganizing the acto-myosin cytoskeleton to drive filopodia extension and contractility. Concurrently, outer blastomeres undergo polarization, with apical domains emerging opposite to contact sites, establishing radial asymmetry that influences subsequent cell fate decisions. Following compaction, cavity formation initiates the transition to the blastocyst stage, typically around the 32-cell stage, through the accumulation of fluid within the embryo to create the blastocoel. This process is driven by the Na+/K+-ATPase pump localized in the basolateral membrane of trophectoderm cells, which actively transports sodium ions out of the cells, creating an osmotic gradient that draws water inward via aquaporins and hydraulic fracturing at cell contacts. The resulting blastocoel expansion separates the outer trophectoderm layer, which forms a polarized epithelium, from the inner cell mass (ICM), a cluster of pluripotent cells positioned at one pole. As the matures, it prepares for implantation by hatching from the , the glycoprotein shell surrounding the . In humans, this occurs around days 5-6 post-fertilization, when expansion thins and ruptures the zona, allowing the to emerge and interact with the uterine . The ICM differentiates into the proper, giving rise to all fetal tissues including the three germ layers, while the trophectoderm develops into extraembryonic structures such as the , facilitating nutrient exchange and implantation. This lineage segregation is essential for successful , as disruptions in ICM or trophectoderm formation lead to developmental arrest.

Meroblastic Cleavage Patterns

Discoidal Cleavage

Discoidal cleavage is a form of meroblastic cleavage observed in telolecithal eggs with substantial reserves, where mitotic divisions are restricted to a small, yolk-free cytoplasmic disc located at the animal pole, leaving the underlying mass undivided. This pattern contrasts with holoblastic cleavage by limiting cell divisions to the blastodisc, a flattened mound of cytoplasm atop the , thereby preventing furrows from penetrating the nutrient-rich . Characteristic of certain vertebrates, including , reptiles, and some species, discoidal cleavage features initial meridional (vertical) divisions followed by equatorial (horizontal) cleavages within the blastodisc, resulting in a multilayered blastoderm of 5–6 cell layers thick while the remains intact below. In bird embryos, such as the domestic , the blastodisc measures approximately 2–3 mm in diameter and differentiates into the central area pellucida, which forms the embryo proper, and area opaca, which contributes to extraembryonic structures. Similarly, in like the , rapid synchronous divisions occur every 15 minutes for the first 12 cycles, forming a mound-shaped blastoderm atop a cell without invading the . The process begins post-fertilization with cytoplasmic rearrangements that concentrate yolk-free material at the animal pole, followed by the first central cleavage furrow that bisects the blastodisc into two cells. Subsequent divisions—vertical and horizontal—proliferate cells within this disc, establishing a single-layered initially that thickens over time, while cells remain connected to the via marginal zones that influence . By the midblastula transition in , zygotic transcription initiates, marking the shift from maternal to embryonic control, and in birds, this leads to formation beneath the epiblast, prefiguring . This cleavage pattern holds significant adaptive value for large-yolked eggs, enabling efficient nutrient utilization by confining rapid cellular proliferation to a compact region, which supports prolonged embryogenesis without depleting the prematurely. It facilitates the establishment of embryonic axes and germ layers, as seen in the differentiation of the blastodisc into structures essential for further development, such as the in avian embryos.

Superficial Cleavage

Superficial cleavage is a type of meroblastic cleavage observed in centrolecithal eggs, where the is concentrated in the center of the , and cell divisions are restricted to the thin peripheral layer of surrounding the uncleaved yolk mass. This pattern is characteristic of certain , particularly arthropods such as , where the large central yolk prevents complete division of the into separate blastomeres. In eggs undergoing superficial cleavage, the initial embryonic divisions occur without , resulting in multiple nuclei within a shared , or , that envelops the central . For example, in the fruit fly Drosophila melanogaster, the first nine nuclear divisions take place deep within the embryo, producing approximately 512 nuclei that then migrate toward the periphery. Subsequent divisions (cycles 10–13) occur at the surface, forming a syncytial blastoderm with roughly 6,000 nuclei embedded in the cortical , still without cell membranes separating them. This syncytial stage allows for rapid nuclear proliferation, as the absence of avoids the mechanical constraints imposed by on cell separation. Following the syncytial blastoderm formation, cellularization begins during nuclear cycle 14, where actin-based invaginations of the plasma membrane surround each nucleus, partitioning the into individual cells to form the cellular blastoderm. This is highly synchronized and adapted to the centrolecithal architecture, enabling efficient development despite the massive, non-dividing core that provides nutrients for the growing . The superficial cleavage pattern thus facilitates accelerated early embryogenesis in by prioritizing nuclear multiplication over immediate compartmentalization.

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