The Cleavage Furrow: A Key Player in Cytokinesis

Maria
Biology
08 Jul, 2024

The cleavage furrow is a critical structure involved in cytokinesis, the final step of cell division in eukaryotic cells, where the cytoplasm is divided to form two daughter cells. This article delves into the structure, formation, mechanisms, and significance of the cleavage furrow, providing a comprehensive understanding of its role in cell biology.

cleavage furrow

Structure of the Cleavage Furrow

The cleavage furrow is a contractile ring composed of various cytoskeletal and regulatory proteins:

Actin Filaments: These are crucial in the cleavage furrow during cytokinesis, forming a contractile ring that pinches the cell into two. Powered by myosin motor proteins, these filaments generate the necessary force for membrane constriction, ensuring the equal division of the cytoplasm and organelles into daughter cells.
Myosin II Motors: These motor proteins generate contractile force by interacting with actin filaments, driving the constriction of the furrow. This action facilitates the separation of the dividing cell into two daughter cells, ensuring proper cellular division and distribution of cytoplasmic contents.
Associated Proteins: Proteins include actin and myosin, forming the contractile ring, and regulatory proteins like RhoA, which organizes actin dynamics. Scaffold proteins such as anillin and septins stabilize the structure, ensuring successful cytokinesis by coordinating membrane addition and constriction to divide the cell into two daughter cells.

Formation of the Cleavage Furrow

The formation of the cleavage furrow is a highly regulated process that occurs in several stages:

Initiation

Spindle Positioning: Spindle positioning ensures the cleavage furrow forms at the cell's equator. This involves astral microtubules, cortical cues, and the centralspindlin complex, coordinating accurate division and equal distribution of chromosomes.
Centralspindlin Complex: The centralspindlin complex, comprising MKLP1 and CYK-4, localizes at the spindle midzone, recruiting Ect2 to activate RhoA, facilitating contractile ring assembly and cleavage furrow ingression during cytokinesis.

Assembly

RhoA Activation: RhoA, a small GTPase, becomes active at the cell equator, promoting the assembly of the contractile ring by recruiting formins to nucleate actin filaments and activating ROCK to stimulate myosin II, driving the furrow's ingression and cell division.
Actin Filament Formation: It begins with RhoA activation, stimulating formin proteins to nucleate actin polymerization. Concurrently, myosin II binds actin filaments, generating contractile force. Anillin and other scaffold proteins stabilize actin organization, facilitating furrow ingression and ensuring successful cell division during cytokinesis.
Myosin II Recruitment: This involves its activation and localization to the contractile ring during cytokinesis. RhoA activation triggers myosin II phosphorylation, promoting its binding to actin filaments. This interaction generates contractile force, essential for furrow ingression and successful division of the cell into two daughter cells.

Constriction

Actomyosin Contraction: It is driven by myosin II interacting with actin filaments. ATP hydrolysis powers this interaction, generating contractile force essential for furrow ingression during cytokinesis.
Membrane Ingression: As the contractile ring tightens, the plasma membrane is pulled inward, leading to the physical separation of the cytoplasm.

Mechanisms of Cleavage Furrow Ingression

The ingression of the cleavage furrow is driven by several coordinated mechanisms:

Actomyosin Contraction

Sliding Filament Model: Myosin II motors walk along actin filaments, sliding them past each other and generating contractile force.
ATP Hydrolysis: It powers the contractile machinery, specifically myosin II, enabling it to interact with actin filaments. This interaction generates the force necessary for furrow ingression during cytokinesis.

Membrane Dynamics

Vesicle Trafficking: This involves the delivery of membrane-bound vesicles to the site of cytokinesis. Regulated by molecular motors and cytoskeletal elements, vesicles fuse with the plasma membrane, supplying new lipid bilayers and membrane proteins. This process supports furrow ingression and facilitates the division of the cell into two daughter cells.
Membrane Recycling: This involves the retrieval and redistribution of membrane components after furrow ingression during cytokinesis. This process is facilitated by endocytic machinery, including clathrin-coated vesicles and dynamin. It ensures the efficient recycling of membrane materials and proteins, contributing to cell membrane integrity and function post-division.

Regulation of Contractile Ring Dynamics

Phosphorylation and Dephosphorylation: Regulatory proteins such as kinases and phosphatases modulate the activity of myosin II and other contractile ring components, fine-tuning the contraction process.
Signal Transduction Pathways: Various signaling pathways, including those involving RhoA, ensure the spatial and temporal regulation of cleavage furrow formation and ingression.

Functions and Significance of the Cleavage Furrow

The cleavage furrow is essential for several key cellular processes:

Cytokinesis

Physical Separation: The cleavage furrow facilitates the physical separation of the cytoplasm, resulting in two daughter cells with equal and distinct cellular components.
Genomic Integrity: By ensuring accurate division of the cytoplasm and its contents, the cleavage furrow helps maintain genomic integrity and cellular function in daughter cells.

Development and Growth

Embryogenesis: Cleavage furrow formation is critical during early embryonic development, where rapid cell divisions generate the multicellular structure of the organism.

Embryogenesis

Tissue Repair and Regeneration: In multicellular organisms, the cleavage furrow plays a role in tissue repair and regeneration by facilitating cell division and the replenishment of damaged or lost cells.

Disease and Dysfunction

Cancer: Dysregulation of cleavage furrow formation and cytokinesis can lead to aneuploidy and contribute to the development and progression of cancer.
Genetic Disorders: Mutations in genes encoding cleavage furrow components can result in genetic disorders characterized by defects in cell division and development.

Research and Advances

Ongoing research continues to unravel the complexities of cleavage furrow formation and function:

Molecular and Cellular Studies

Live-Cell Imaging: Advanced microscopy techniques allow real-time observation of cleavage furrow dynamics, providing insights into the molecular mechanisms of cytokinesis.
Genetic and Biochemical Approaches: Gene editing and biochemical assays help identify and characterize the roles of various proteins involved in cleavage furrow formation and regulation.

Therapeutic Implications

Cancer Therapy: Targeting cleavage furrow components and cytokinesis regulators holds potential for the development of novel cancer therapies aimed at disrupting aberrant cell division.
Regenerative Medicine: Understanding cleavage furrow dynamics can inform strategies for tissue engineering and regenerative medicine, promoting efficient cell division and tissue repair.

Cleavage Furrow FAQ

The formation and ingression of the cleavage furrow during cytokinesis are driven by a complex interplay of molecular mechanisms:

Actomyosin Contraction: The cleavage furrow is primarily formed by a contractile ring composed of actin filaments and myosin II motors. Myosin II generates contractile force by sliding actin filaments past each other, which is powered by ATP hydrolysis.
RhoA Activation: RhoA, a small GTPase, is activated at the cell equator and plays a crucial role in regulating the assembly of the contractile ring. RhoA activates formins, which nucleate actin filament formation, and Rho-kinase (ROCK), which activates myosin II through phosphorylation.
Centralspindlin Complex: This protein complex, consisting of MKLP1 and CYK-4, localizes to the spindle midzone and recruits other proteins essential for cleavage furrow formation, such as Ect2, which further activates RhoA.
Membrane Dynamics: Vesicle trafficking and membrane addition at the cleavage furrow are essential for furrow ingression. Proteins like SNAREs facilitate the fusion of vesicles with the plasma membrane, adding new membrane material as the furrow ingresses.

The position of the cleavage furrow is determined by several factors, primarily involving the mitotic spindle and signaling molecules:

Spindle Midzone and Astral Microtubules: The mitotic spindle, especially the spindle midzone and astral microtubules, plays a key role in positioning the cleavage furrow. The central spindle sends signals that specify the cell equator as the site for furrow formation.
Centralspindlin and Chromosomal Passenger Complex: These complexes accumulate at the central spindle and the cell cortex at the prospective division site, marking the position for the cleavage furrow. Aurora B kinase, a component of the Chromosomal Passenger Complex, helps regulate this process.
Cortical Cues: The cell cortex, influenced by the spatial organization of the actin cytoskeleton and the localization of proteins like anillin, also helps determine the furrow position by reinforcing signals from the spindle apparatus.

Anillin and other scaffold proteins play critical roles in stabilizing and promoting the ingression of the cleavage furrow:

Anillin: Anillin acts as a scaffold protein that links the actomyosin contractile ring to the plasma membrane. It interacts with actin, myosin II, and other membrane-associated proteins to ensure the proper assembly and stabilization of the contractile ring.
Septins: Septins are GTP-binding proteins that form filamentous structures at the cleavage furrow. They provide structural support and act as a diffusion barrier, ensuring the localization and retention of proteins necessary for furrow ingression.
Formins: Formins nucleate and elongate actin filaments, contributing to the dynamic reorganization of the actin cytoskeleton required for furrow ingression. They are activated by RhoA and help maintain the structure of the contractile ring.
IQGAPs: IQGAP proteins interact with actin and other signaling molecules, coordinating the cytoskeletal dynamics and ensuring the contractile ring's proper function during cytokinesis.

Signaling pathways tightly regulate the dynamics of the cleavage furrow to ensure successful cytokinesis:

RhoA Pathway: RhoA is a central regulator of the cleavage furrow. Its activation leads to the recruitment and activation of downstream effectors such as formins (for actin nucleation) and ROCK (for myosin II activation). RhoA activity is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs).
Centralspindlin Complex and Ect2: The centralspindlin complex recruits Ect2, a RhoGEF, to the central spindle and cell cortex. Ect2 activates RhoA, initiating the assembly and contraction of the actomyosin ring.
Aurora B Kinase: Part of the Chromosomal Passenger Complex, Aurora B kinase regulates cleavage furrow formation by phosphorylating key proteins involved in cytokinesis. It ensures the proper localization of the centralspindlin complex and other regulatory proteins at the division site.
Cyclin-dependent Kinases (CDKs): CDKs regulate the progression of the cell cycle and the initiation of cytokinesis. CDK1, in particular, is involved in the transition from mitosis to cytokinesis by regulating the disassembly of the mitotic spindle and the formation of the cleavage furrow.

Defective cleavage furrow formation and ingression can have severe consequences, leading to various diseases and developmental disorders:

Aneuploidy: Improper cleavage furrow ingression can result in the unequal segregation of chromosomes, leading to aneuploidy. This condition is associated with various diseases, including Down syndrome, Turner syndrome, and certain cancers.
Cytokinesis Failure: Complete failure of the cleavage furrow can result in binucleate or multinucleate cells, which can lead to abnormal cell function, impaired tissue development, and increased susceptibility to cancer.
Cancer: Defects in proteins involved in cleavage furrow formation, such as mutations in anillin, myosin II, or regulatory kinases like Aurora B, can contribute to tumorigenesis. These defects may cause chromosomal instability, a hallmark of many cancers.
Developmental Disorders: Proper cleavage furrow function is crucial during embryonic development. Defects in cytokinesis can lead to developmental abnormalities and diseases due to impaired cell division and differentiation processes.

Conclusion

The cleavage furrow is a vital structure in cell biology, ensuring the successful completion of cytokinesis and the formation of two daughter cells. Its intricate formation and regulation involve a complex interplay of cytoskeletal components, signaling pathways, and cellular dynamics. Continued research into the cleavage furrow will deepen our understanding of cell division and its implications for development, disease, and therapeutic interventions, highlighting its significance as a key player in cellular life.

Read this article on cleavage furrow positioning https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915198/

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