What is the Cleavage Furrow? A Comprehensive Guide

The process of cell division, crucial for growth and repair in organisms, culminates in cytokinesis, where the cell physically divides into two daughter cells. One key event during animal cell cytokinesis is the formation of the cleavage furrow, a contractile ring-driven structure. Myosin II, a motor protein, plays a critical role in the assembly and constriction of this furrow. Understanding the mechanics of the cleavage furrow is essential for developmental biology research, especially in the context of understanding diseases like cancer, where unregulated cell division occurs. Thus, this comprehensive guide elucidates what is the cleavage furrow, its formation, and its significance in cell division.

Unveiling the Cleavage Furrow: The Key to Cell Division

The cleavage furrow is a critical structure in cell division, specifically during cytokinesis.

It marks the physical division of a cell into two daughter cells.

This seemingly simple indentation of the cell membrane represents a complex interplay of molecular events.

It is essential for the accurate partitioning of cellular material.

Defining the Cleavage Furrow

At its core, the cleavage furrow is defined as an indentation or constriction of the cell membrane.

This indentation signals the start of cytokinesis in animal cells.

Unlike cell division in plants, which involves the formation of a cell plate, animal cells rely on the contractile mechanism of the cleavage furrow to physically separate.

The furrow deepens progressively, eventually pinching the cell in two.

Significance in Cell Division

The formation and progression of the cleavage furrow is not merely a physical separation event.

It is crucial for the accurate distribution of chromosomes and other cellular components between the newly forming daughter cells.

Failure in this process can lead to aneuploidy.

Aneuploidy is a condition where cells have an abnormal number of chromosomes, which can have devastating consequences, including cell death or the development of diseases like cancer.

The cleavage furrow ensures that each daughter cell receives a complete and functional set of genetic material.

Importance in Early Embryonic Development

The cleavage furrow plays an especially crucial role in early embryonic development.

Following fertilization, the zygote undergoes a series of rapid cell divisions known as cleavage.

These divisions, facilitated by the cleavage furrow, increase the number of cells without significantly increasing the overall size of the embryo.

The precise positioning and timing of cleavage furrows during these early divisions are critical for establishing cell fates and laying the foundation for the developing organism's body plan.

Errors in cleavage furrow formation during this stage can lead to severe developmental abnormalities.

Unveiling the Cleavage Furrow: The Key to Cell Division

The cleavage furrow is a critical structure in cell division, specifically during cytokinesis.

It marks the physical division of a cell into two daughter cells.

This seemingly simple indentation of the cell membrane represents a complex interplay of molecular events.

It is essential for the accurate partitioning of cellular material.

The Contractile Ring: The Engine of Cell Division

While the cleavage furrow is the visible manifestation of cell division, the true engine driving this process is the contractile ring.

This dynamic structure, assembled beneath the plasma membrane at the site of furrow formation, is responsible for generating the force necessary to physically cleave the cell in two.

Understanding the contractile ring is paramount to grasping the mechanics of cytokinesis.

Composition of the Contractile Ring: Actin and Myosin

The contractile ring's primary components are actin filaments and myosin II motor proteins.

Actin filaments, arranged circumferentially within the ring, provide the structural framework.

Myosin II interacts with these actin filaments to generate the contractile force.

This interaction is analogous to muscle contraction, where myosin slides along actin filaments, leading to a reduction in ring circumference.

Actin Filaments: The Scaffold

Actin filaments within the contractile ring are not simply a static scaffold.

They are constantly being remodeled through polymerization and depolymerization.

This dynamic turnover is essential for the ring's ability to constrict and adapt to the changing geometry of the dividing cell.

The precise organization and orientation of these filaments are critical for effective force generation.

Myosin II: The Molecular Motor

Myosin II, a motor protein, is the key player in generating the force required for constriction.

It uses the energy from ATP hydrolysis to "walk" along actin filaments, pulling them towards each other.

This sliding action causes the contractile ring to shrink in diameter, effectively pinching the cell membrane inward.

The activity of myosin II is tightly regulated, ensuring that constriction occurs at the appropriate time and location.

Regulating Ring Assembly and Constriction

The assembly and constriction of the contractile ring are not spontaneous events.

They are tightly regulated by a complex network of signaling pathways and regulatory proteins.

This precise regulation ensures that cytokinesis is coordinated with other stages of the cell cycle and that cell division occurs accurately.

Errors in this regulation can lead to failed cell division and potentially detrimental consequences.

RhoA, a small GTPase, is a master regulator of contractile ring formation and function.

It acts as a molecular switch, cycling between an inactive (GDP-bound) and an active (GTP-bound) state.

In its active state, RhoA recruits and activates downstream effectors that promote actin polymerization and myosin II activation.

The spatial and temporal activation of RhoA is crucial for precisely positioning the contractile ring at the cell's equator.

Several other proteins play essential roles in regulating the contractile ring.

Formins are actin-nucleating proteins that promote the formation of new actin filaments.

Proteins like profilin enhance actin polymerization by delivering actin monomers to the growing filament ends.

Anillin acts as a scaffolding protein, linking the contractile ring to the plasma membrane and other cytoskeletal components.

These proteins work together to ensure the proper assembly, stability, and function of the contractile ring.

Key Players: Proteins Orchestrating the Cleavage Furrow

The formation and execution of the cleavage furrow are not spontaneous events. It is instead a finely tuned process orchestrated by a symphony of proteins.

These molecular players work in concert to ensure that the cell divides accurately and efficiently. Understanding their individual roles, as well as their interactions, is crucial for a complete appreciation of cytokinesis.

Myosin II: The Force-Generating Motor

At the heart of the contractile ring lies myosin II, a motor protein that interacts directly with actin filaments to generate the force necessary for furrow ingression.

Myosin II is not just a passive structural component; it actively participates in the constriction process.

This protein utilizes the energy derived from ATP hydrolysis to "walk" along actin filaments, effectively pulling them closer together.

This sliding filament mechanism reduces the circumference of the contractile ring, driving the inward movement of the plasma membrane and ultimately cleaving the cell.

RhoA: The Master Regulator of Contractility

The activity of myosin II, and thus the overall contractility of the ring, is tightly controlled by RhoA, a small GTPase that functions as a master regulator.

RhoA acts as a molecular switch, cycling between an inactive (GDP-bound) and an active (GTP-bound) state.

When activated, RhoA initiates a signaling cascade that leads to the activation of downstream effectors, including Rho-associated kinase (ROCK).

ROCK, in turn, phosphorylates myosin light chain (MLC), enhancing myosin II activity and promoting actin-myosin interaction.

The precise spatial and temporal activation of RhoA is critical for positioning the contractile ring at the cell's equator and ensuring that constriction occurs at the appropriate stage of the cell cycle.

Formins: Architects of Actin Filaments

Formins are a family of actin-nucleating proteins that play a vital role in the dynamic assembly and organization of actin filaments within the contractile ring.

Unlike other actin-nucleating factors, formins remain associated with the growing plus ends of actin filaments, protecting them from capping proteins and facilitating processive polymerization.

This processive elongation is crucial for the formation of long, unbranched actin filaments that provide the structural framework for the contractile ring.

Different formin isoforms may be involved in regulating different aspects of actin filament dynamics during cytokinesis, highlighting the complexity of this process.

Profilin: Fueling Actin Polymerization

Profilin is an actin-binding protein that plays a critical role in sustaining the rapid actin polymerization required for contractile ring assembly and constriction.

Profilin binds to actin monomers, promoting the exchange of ADP for ATP and facilitating the addition of these monomers to the barbed ends of actin filaments.

By increasing the local concentration of ATP-bound actin monomers, profilin enhances the rate of actin polymerization and ensures that the contractile ring has a sufficient supply of building blocks to maintain its structure and function.

A Concerted Effort: Ensuring Accurate Cleavage

These proteins, along with many others, do not act in isolation.

They engage in complex interactions and regulatory networks to ensure that the cleavage furrow forms at the right time and place, and that it constricts in a coordinated manner.

RhoA regulates myosin II activity and also influences formin-mediated actin polymerization.

Profilin, by promoting actin polymerization, provides the substrate for myosin II-driven contraction.

This intricate interplay highlights the importance of viewing cytokinesis as a collaborative process, rather than a series of independent events.

Disruptions in the function of any of these key players can lead to errors in cell division, potentially resulting in aneuploidy and other detrimental consequences.

Regulation and Signaling: Coordinating Cell Division

The seemingly simple act of cell division is, in reality, a highly orchestrated process. The formation and progression of the cleavage furrow are not autonomously driven; rather, they are precisely controlled by a network of intricate cell signaling pathways.

These pathways act as communication lines, ensuring that cytokinesis is synchronized with other crucial cellular events, particularly those occurring during mitosis.

Understanding the regulatory mechanisms that govern cleavage furrow formation is essential for comprehending the fidelity of cell division and its implications for development and disease.

The Importance of Temporal Control

The timing of cleavage furrow initiation is paramount. It must occur precisely at the transition from metaphase to anaphase, ensuring that the duplicated chromosomes have been properly segregated to opposite poles of the cell.

Premature or delayed furrow formation can lead to unequal chromosome distribution, resulting in aneuploidy – a condition often associated with developmental abnormalities and cancer.

The anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase, plays a crucial role in this temporal regulation. By targeting specific proteins for degradation, the APC/C triggers the metaphase-anaphase transition, simultaneously activating signaling cascades that initiate furrow formation.

Spatial Control: Positioning the Cleavage Furrow

Equally important is the spatial control of cleavage furrow formation. The furrow must form precisely at the cell's equator, ensuring that the resulting daughter cells receive equal complements of chromosomes and cytoplasm.

The spindle apparatus, with its emanating microtubules, plays a critical role in defining this equatorial plane. Signals originating from the spindle midzone, the region where microtubules from opposite poles overlap, recruit and activate key regulators of furrow formation to the cell cortex.

This ensures that the contractile ring assembles at the correct location, perpendicular to the spindle axis.

RhoA Signaling: A Central Hub

Among the many signaling pathways involved in cleavage furrow regulation, the RhoA pathway stands out as a central hub. As previously discussed, RhoA is a small GTPase that controls actin-myosin contractility, the driving force behind furrow ingression.

However, RhoA's activity is itself tightly regulated by a variety of upstream signals. These signals, originating from the spindle apparatus and other cellular cues, activate RhoA at the cell cortex, leading to the localized assembly and constriction of the contractile ring.

Furthermore, RhoA activity is spatially restricted, ensuring that contraction occurs only at the desired location. This spatial restriction is achieved through the action of Rho guanine nucleotide exchange factors (GEFs), which activate RhoA, and Rho GTPase-activating proteins (GAPs), which inactivate RhoA.

Crosstalk and Feedback Loops

The regulation of cleavage furrow formation is not a linear process; it involves significant crosstalk and feedback loops between different signaling pathways.

For example, the APC/C not only triggers anaphase but also influences RhoA activity, directly linking chromosome segregation to furrow formation.

Similarly, the contractile ring itself can generate signals that modulate its own activity, creating a self-reinforcing feedback loop that ensures efficient furrow ingression.

These complex interactions highlight the robustness and adaptability of the cleavage furrow formation process, allowing it to respond to changing cellular conditions and ensure accurate cell division.

Disruptions in Signaling: Consequences for Cell Division

Given the complexity of the regulatory mechanisms governing cleavage furrow formation, it is not surprising that disruptions in these pathways can have severe consequences.

Defects in RhoA signaling, for example, can lead to furrowing failure, resulting in binucleated cells or aneuploidy.

Similarly, mutations in genes encoding spindle assembly checkpoint proteins can disrupt the timing of furrow formation, leading to premature or delayed cytokinesis.

These errors in cell division can contribute to developmental defects, genomic instability, and cancer progression, underscoring the importance of maintaining the integrity of the signaling pathways that control cleavage furrow formation.

Cytokinesis and Mitosis: A Synchronized Dance

The formation of the cleavage furrow is not an isolated event, but rather an integral part of the broader cell division process encompassing both mitosis and cytokinesis.

These two processes, while distinct, are meticulously coordinated to ensure the faithful segregation of chromosomes and the subsequent division of the cell into two genetically identical daughter cells.

The cleavage furrow is the physical manifestation of cytokinesis, and its precise execution hinges on the successful completion of mitosis.

The Cleavage Furrow as the Driver of Cytokinesis

Cytokinesis, the physical division of the cell, is directly driven by the constriction of the cleavage furrow.

The contractile ring, composed of actin and myosin filaments, generates the force required to progressively pinch the cell membrane inward, eventually leading to complete separation.

This process is far from passive; it requires a constant supply of energy and a complex interplay of signaling molecules to ensure that the furrow ingresses uniformly and efficiently.

Without the cleavage furrow, the duplicated chromosomes would remain within a single cell, resulting in polyploidy.

The Intimate Coordination of Cytokinesis and Mitosis

Cytokinesis and mitosis are not simply sequential events; they are tightly interwoven, with the successful completion of each phase depending on the proper execution of the other.

The cell employs a variety of checkpoints and signaling pathways to monitor the progress of mitosis and ensure that cytokinesis does not begin prematurely or before chromosome segregation is complete.

This coordination is essential for maintaining genomic stability and preventing the formation of aneuploid cells.

Anaphase: The Green Light for Cleavage Initiation

Anaphase, the stage of mitosis during which sister chromatids separate and move to opposite poles of the cell, plays a crucial role in signaling the initiation of cleavage furrow formation.

The transition from metaphase to anaphase triggers a cascade of events that ultimately lead to the activation of RhoA, the master regulator of actin-myosin contractility.

This activation occurs primarily at the cell equator, precisely where the cleavage furrow is destined to form.

The spatial control of RhoA activation is achieved through the action of various signaling molecules, including the centralspindlin complex, which accumulates at the spindle midzone during anaphase.

This complex recruits and activates RhoGEFs, which in turn activate RhoA at the cell cortex.

In essence, anaphase serves as the "green light" for cytokinesis, ensuring that the cleavage furrow forms only after the chromosomes have been properly segregated.

The Spindle Apparatus: Guiding the Furrow's Formation

The mitotic spindle, a dynamic structure composed of microtubules, plays a pivotal role not only in chromosome segregation but also in orchestrating cytokinesis. Its influence extends to both the positioning and timing of cleavage furrow formation, ensuring accurate cell division.

The spindle's central importance lies in its ability to transmit signals that dictate where and when the cell should divide, thereby coordinating the physical act of division with the successful completion of chromosome segregation.

Spindle Positioning and Furrow Placement

The location of the cleavage furrow is not arbitrary; it is precisely determined by the position of the mitotic spindle. The spindle's midzone, the region between the separating chromosomes, sends out signals that specify the site of furrow ingression.

This ensures that the cell divides along a plane perpendicular to the spindle axis, resulting in two daughter cells that each receive a complete set of chromosomes.

Astral Microtubules and Cortical Interactions

The astral microtubules, emanating from the spindle poles and extending towards the cell cortex, play a crucial role in positioning the spindle and, consequently, the cleavage furrow. These microtubules interact with the cell cortex, influencing the distribution of cortical proteins involved in furrow formation.

Disruptions in astral microtubule dynamics can lead to mispositioned spindles and aberrant cleavage furrow formation, resulting in unequal chromosome segregation and potentially aneuploidy.

Experimental evidence has demonstrated that manipulating astral microtubule length or stability directly affects spindle positioning and the subsequent location of the cleavage furrow.

Spindle Signals and Temporal Control

Beyond its role in positioning, the spindle also regulates the timing of cleavage furrow formation. The transition from metaphase to anaphase triggers a cascade of signaling events that ultimately activate the contractile ring.

This ensures that cytokinesis begins only after the chromosomes have been properly segregated, preventing premature or incomplete division.

The Centralspindlin Complex and RhoA Activation

A key player in this temporal control is the centralspindlin complex, which accumulates at the spindle midzone during anaphase. This complex recruits and activates Rho guanine nucleotide exchange factors (RhoGEFs), which in turn activate RhoA, the master regulator of actin-myosin contractility.

The precise spatial and temporal regulation of RhoA activation is essential for ensuring that the cleavage furrow forms only at the appropriate time and location. Without this regulation, the cell division process would be prone to errors, leading to genomic instability.

The centralspindlin complex acts as a critical bridge, linking chromosome segregation to the initiation of cytokinesis. Its disruption leads to failure in furrow formation and subsequent cell division defects.

Post-Cleavage: The Midbody's Role

As cytokinesis nears completion, a slender intercellular bridge persists, connecting the newly forming daughter cells. This structure, known as the midbody, is far from a mere remnant of cell division. It's a dynamic and complex entity that plays a crucial role in the final act of cell separation, termed abscission.

Understanding the midbody's formation, composition, and function is essential for a complete picture of cell division and its implications for development and disease.

Defining the Midbody: An Intercellular Bridge

The midbody is best defined as the transient intercellular bridge that connects two daughter cells toward the end of cytokinesis.

It's a dense, protein-rich structure that originates from the central spindle midzone, the region between separating chromosomes during anaphase.

As the contractile ring constricts, the midzone microtubules become bundled together, forming the core of the midbody.

This structure serves as a platform for the recruitment of numerous proteins essential for abscission.

Midbody Formation: A Step-by-Step Process

The formation of the midbody is a precisely orchestrated process, intimately linked to the progression of cytokinesis.

It begins with the bundling of antiparallel microtubules at the spindle midzone during anaphase. These microtubules are stabilized and organized by proteins such as centralspindlin.

As the contractile ring constricts, these bundled microtubules are compacted into a dense structure.

Subsequently, various proteins involved in abscission, including ESCRT-III components, accumulate at the midbody, preparing it for the final cell separation.

Composition of the Midbody: A Proteinaceous Hub

The midbody is not simply a collection of microtubules; it is a complex assembly of proteins. Several key proteins are essential for its structure and function.

These proteins include:

• Microtubule-associated proteins: These proteins, such as PRC1, stabilize and organize the midzone microtubules.

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• Centralspindlin components: These proteins, including MKLP1 and CYK-4, recruit other proteins to the midbody and regulate RhoA activity.

• ESCRT-III components: The ESCRT-III machinery is crucial for membrane scission during abscission.

• Abscission-regulating kinases: These kinases, such as Aurora B, regulate the activity of other proteins involved in abscission.

The precise composition of the midbody can vary depending on cell type and developmental stage, reflecting the diverse roles it plays in different cellular contexts.

The Midbody's Role in Abscission: The Final Cut

The primary role of the midbody is to facilitate abscission, the final physical separation of the two daughter cells. This process involves the constriction and severing of the intercellular bridge at the midbody.

The ESCRT-III machinery plays a critical role in this process, mediating membrane remodeling and scission. ESCRT-III filaments polymerize at the midbody, constricting the membrane and ultimately leading to its severing.

The timing of abscission is tightly regulated to ensure that it occurs only after chromosome segregation is complete and the daughter cells are properly formed.

Beyond Abscission: Additional Functions of the Midbody

While its role in abscission is paramount, the midbody is increasingly recognized to have other functions as well.

These include:

• Signaling: The midbody can act as a signaling platform, influencing cell fate and behavior.

• Quality control: The midbody can help to ensure that damaged or abnormal cells are eliminated.

• Cellular Memory: Recent evidence suggests the midbody remnant can be inherited by one daughter cell, influencing its fate, potentially contributing to cellular asymmetry and differentiation.

Further research is needed to fully elucidate the diverse functions of the midbody and its impact on cellular processes.

Midbody Remnants: Fates and Implications

After abscission, a portion of the midbody remains attached to one or both of the daughter cells, forming a midbody ring or a midbody remnant.

These remnants can be degraded, or they can persist for some time, potentially influencing cell behavior.

Aberrant midbody persistence has been linked to various diseases, including cancer, highlighting the importance of proper midbody regulation.

Cleavage Furrow in Embryonic Development: Building Blocks of Life

The cleavage furrow isn't just a cellular mechanism; it's a fundamental force shaping the earliest stages of life. In the immediate aftermath of fertilization, the single-celled zygote embarks on a journey of rapid cell division, known as cleavage. This period is characterized by a flurry of mitotic events, driven by the precise formation and execution of the cleavage furrow, transforming the zygote into a multicellular embryo.

The Rush of Early Cleavage Divisions

Unlike typical cell divisions that incorporate significant growth phases, cleavage divisions are unique. They bypass the G1 and G2 phases of the cell cycle. This allows for rapid cell proliferation without an increase in overall embryonic size. The zygote essentially subdivides its existing cytoplasm into smaller and smaller cells.

These initial divisions are critically dependent on the efficient and timely formation of the cleavage furrow. Without it, the embryo would fail to progress beyond a single cell.

Initial Furrow Formation in the Zygote

The zygote, the newly formed cell resulting from the fusion of sperm and egg, represents the starting point of embryonic development. The first cleavage furrow formation is a defining moment. It initiates the transformation from a single cell to a multicellular organism.

This initial furrow is meticulously positioned and precisely executed to ensure the equal or unequal partitioning of the zygote's contents. The location of the first cleavage is frequently influenced by factors such as the sperm entry point and maternal determinants already present in the egg.

Blastomeres: The First Generation of Cells

As the zygote undergoes cleavage, it gives rise to a population of cells called blastomeres. These are the building blocks of the developing embryo. Each division creates more blastomeres, progressively reducing the size of each individual cell while increasing the overall cell number.

The fate of these early blastomeres is not always fixed; they can retain a remarkable degree of developmental plasticity, especially in the very early stages. This plasticity allows for adjustments and compensations in response to environmental cues or developmental challenges.

Cell Polarity and Furrow Orientation

Cell polarity, the asymmetric organization of cellular components, plays a crucial role in influencing the positioning and orientation of the cleavage furrow. This is particularly relevant in embryos that undergo unequal cleavage, where daughter cells inherit different cytoplasmic determinants and adopt distinct developmental fates.

Maternal factors, pre-existing asymmetries within the egg, and cell-cell signaling can all contribute to establishing cell polarity, ultimately dictating the direction and angle of the cleavage furrow. This ensures proper segregation of developmental signals.

Tools of Discovery: Researching the Cleavage Furrow

Unraveling the intricacies of the cleavage furrow requires a combination of astute experimental design and powerful research tools. Scientists employ a variety of model organisms and sophisticated imaging techniques to observe, manipulate, and understand the dynamic processes underlying cell division. These approaches have provided invaluable insights into the molecular mechanisms that drive furrow formation and ensure accurate cell separation.

The Sea Urchin Advantage: A Classic Model Organism

Sea urchins have long been a favorite among developmental biologists, and their use in cleavage furrow research is no exception. Several features make them ideally suited for these studies.

First, sea urchin eggs are relatively large and transparent, offering excellent optical clarity for microscopic observation. Second, they can be easily obtained in large quantities and fertilized in vitro, providing a readily accessible and highly synchronous population of dividing cells.

Finally, their relatively simple developmental program and external fertilization make them amenable to experimental manipulations, such as microinjection of fluorescently labeled proteins or RNA interference to knock down specific genes. These advantages have made sea urchins indispensable for visualizing and dissecting the molecular events that govern cleavage furrow formation.

Visualizing the Dynamic Furrow: The Power of Microscopy

Microscopy plays a pivotal role in studying the cleavage furrow. It enables direct visualization of the furrow's dynamic behavior and the underlying molecular components in real-time.

Advanced microscopy techniques, such as time-lapse microscopy and confocal microscopy, provide high-resolution images of the furrow as it forms and constricts.

These techniques can capture the precise movements of actin filaments, myosin motors, and other key proteins, revealing the spatiotemporal dynamics of the contractile ring. Furthermore, live-cell imaging allows researchers to track the assembly and disassembly of the contractile ring, as well as the recruitment of regulatory proteins to the furrow region.

This has greatly contributed to our knowledge of how forces are generated and coordinated during cytokinesis.

Illuminating the Molecular Players: Immunofluorescence and Beyond

While microscopy allows visualization of cellular structures, immunofluorescence provides a powerful means to identify and localize specific proteins within the cleavage furrow.

This technique utilizes antibodies that bind to target proteins, coupled with fluorescent tags, to highlight their distribution and abundance. By using antibodies against actin, myosin, and other key regulators, researchers can map the molecular architecture of the contractile ring and track the recruitment of these proteins to the furrow region.

Immunofluorescence can also be combined with other techniques, such as fluorescence recovery after photobleaching (FRAP), to measure protein dynamics and turnover rates within the furrow. Furthermore, the development of genetically encoded fluorescent proteins has enabled the visualization of protein localization and interactions in living cells, providing even greater insights into the molecular mechanisms underlying cleavage furrow formation. The ability to pinpoint the precise location and behavior of individual proteins has proven invaluable for understanding their roles in this critical process.

So, there you have it! Hopefully, this guide has cleared up any confusion you might have had about what the cleavage furrow is and its crucial role in cell division. Now you can impress your friends with your newfound knowledge of cytokinesis!