The Midbody (MB) & Midbody Remnant (MBR)
Ahna giving a public talk about the history of the midbody and current research in the Skop Lab
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The midbody is a transient yet highly specialized structure formed at the final stage of cell division. Following chromosome segregation during anaphase, an actomyosin contractile ring constricts the central spindle—composed of antiparallel microtubules—into a narrow intercellular bridge connecting the two daughter cells. At the center of this bridge lies the midbody (MB), a ~1–2 µm structure characterized by a dense proteinaceous core known as the midbody matrix. In electron micrographs, this matrix appears as an electron-dense region coating the zone of microtubule overlap and is notably resistant to antibody penetration, giving rise to the term “dark zone.”
A key insight in the field is that abscission does not occur through this central dark zone. Instead, membrane scission takes place on both sides of the matrix, releasing the midbody as a membrane-bound extracellular structure known as the midbody remnant (MBR). This finding reframes the midbody not as a discarded byproduct of cell division, but as a specialized extracellular vesicle. While extracellular vesicles were once thought to primarily mediate cellular waste disposal, they are now recognized as critical vehicles for intercellular communication. Emerging evidence establishes that post-mitotic MBRs are biologically active and capable of influencing recipient cells. However, fundamental questions remain: Is MBR-mediated signaling a general and conserved mode of intercellular communication? What molecular cargo and mechanisms govern information transfer? And does the unique midbody matrix itself play a functional role in signaling? Midbody dysregulation in diseaseHistorically viewed as a vestigial “garbage can” of the cell, the midbody has received limited attention as a therapeutic target. This perspective is rapidly changing. Mutations and dysregulation of midbody-associated proteins are now linked to a wide spectrum of human diseases, including cancer and neurodevelopmental and neurodegenerative disorders. Defects in cytokinesis—such as failed abscission, multinucleation, or uncontrolled proliferation—are associated with pathologies ranging from glioma, lung cancer, and breast cancer to microcephaly and infertility. In neurological contexts, abnormalities in midbody function are linked to conditions such as MARCH syndrome, characterized by multinucleated neurons and severe brain malformations, as well as spinocerebellar ataxia and other disorders involving progressive neurodegeneration and aberrant RNA granule accumulation. Together, these findings position the midbody and its remnants as previously unrecognized regulators of cellular communication and disease biology, with significant implications for diagnostics and therapeutic development. Our lab focuses on understanding the biology and function of the midbody (MB) and midbody remnant (MBR) using mammalian cell culture and stem cell systems.
We investigate how the midbody is assembled during the final stages of mitosis and how its inheritance or release shapes cell fate. To enable these studies, we have developed methods to isolate MBRs from diverse cell types and tissues. Our work has revealed that the MBR represents a distinct class of large extracellular vesicle, uniquely defined by the presence of canonical midbody proteins such as KIF23/MKLP1 and the surprising capacity to support active protein translation. We are now defining how the RNA and protein cargo of MBRs differ across cell types, with a particular focus on cancer and neural systems. In parallel, we study a specialized RNA granule that assembles at the midbody and is selectively packaged into MBRs. We aim to understand how these RNA-rich organelles are regulated during the cell cycle and how they contribute to developmental processes at the organismal level. Finally, we seek to uncover the mechanisms by which MBRs mediate intercellular communication, including how molecular information is transferred between cells and how this signaling influences physiology and disease. |
The Midbody Remnant (MBR)
The midbody remnant (MBR) is a large extracellular vesicle generated during the final step of cell division. Once considered a byproduct of cytokinesis, MBRs are now recognized as functionally active structures that contribute to cell signaling, proliferation, and fate determination.
MBRs contain a distinctive repertoire of ribonucleoproteins, mRNAs, and translational machinery, enabling localized protein synthesis outside the context of the dividing cell. This RNA cargo is enriched for transcripts linked to cell fate regulation, oncogenic pathways, and pluripotency programs.
Following their formation, MBRs can be released into the extracellular environment, retained by daughter cells, internalized by neighboring cells, or targeted for degradation through autophagy. These diverse fates suggest that MBRs represent a regulated and previously underappreciated mechanism of intercellular communication.
Understanding how MBRs are produced, trafficked, and function in recipient cells has important implications for development, tissue homeostasis, and disease, particularly in cancer where cell fate decisions and signaling networks are frequently disrupted.
Recent papers on the MBR from the Skop lab include:
1. Patel S., et al. (2024) Extracellular vesicles, including large translating vesicles called midbody remnants, are released during the cell cycle. Molecular Biology of the Cell
2. Park S, et al. (2023) The mammalian midbody and midbody remnant are assembly sites for RNA and localized translation. Developmental Cell.
3. Park S, et al. (2023) A protocol for isolating and imaging large extracellular vesicles or midbody remnants from mammalian cell culture. STAR Protocols.
4. Jung GI, et al. (2023) An oocyte meiotic midbody cap is required for developmental competence in mice. Nature Communications.
5. Skop AR, Liu H, Yates J 3rd, Meyer BJ, Heald R. Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms. Science
MBRs contain a distinctive repertoire of ribonucleoproteins, mRNAs, and translational machinery, enabling localized protein synthesis outside the context of the dividing cell. This RNA cargo is enriched for transcripts linked to cell fate regulation, oncogenic pathways, and pluripotency programs.
Following their formation, MBRs can be released into the extracellular environment, retained by daughter cells, internalized by neighboring cells, or targeted for degradation through autophagy. These diverse fates suggest that MBRs represent a regulated and previously underappreciated mechanism of intercellular communication.
Understanding how MBRs are produced, trafficked, and function in recipient cells has important implications for development, tissue homeostasis, and disease, particularly in cancer where cell fate decisions and signaling networks are frequently disrupted.
Recent papers on the MBR from the Skop lab include:
1. Patel S., et al. (2024) Extracellular vesicles, including large translating vesicles called midbody remnants, are released during the cell cycle. Molecular Biology of the Cell
2. Park S, et al. (2023) The mammalian midbody and midbody remnant are assembly sites for RNA and localized translation. Developmental Cell.
3. Park S, et al. (2023) A protocol for isolating and imaging large extracellular vesicles or midbody remnants from mammalian cell culture. STAR Protocols.
4. Jung GI, et al. (2023) An oocyte meiotic midbody cap is required for developmental competence in mice. Nature Communications.
5. Skop AR, Liu H, Yates J 3rd, Meyer BJ, Heald R. Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms. Science
Cytokinesis
Cell division is fundamental to the growth, maintenance, and regeneration of all living systems. A key stage occurs after chromosome segregation, when cellular contents—including the cytoplasm and organelles—are partitioned into two daughter cells through cytokinesis. In animal cells, this process is driven by a contractile actomyosin ring that constricts the cell membrane, requiring precise coordination between the mitotic spindle, cytoskeleton, and membrane trafficking pathways. Defects in cytokinesis can lead to cell death, developmental abnormalities, or genome instability, a hallmark of many cancers. Despite more than a century of study, the molecular mechanisms governing cytokinesis—and how its completion is regulated—remain incompletely understood. Our work focuses on how the cleavage furrow is specified, how abscission is executed, and how structures such as the spindle midzone and midbody coordinate the final steps of cell division. To address these questions, our laboratory integrates complementary approaches across mammalian systems and C. elegans, combining proteomics, functional genomics, genetics, advanced imaging, and quantitative cell biology to identify conserved regulatory mechanisms. We have identified critical roles for RNA-binding proteins, including ATX-2/Ataxin-2, in cytokinesis and midbody function. Notably, mutations in Ataxin-2 are linked to human neurodegenerative disease. Building on this, we investigate how midbody-associated mRNAs and RNA-protein complexes contribute not only to cytokinesis itself, but also to post-mitotic functions, including the signaling and regulatory roles of the midbody remnant.
We identified novel ATX-2 interacting proteins in a temperature sensitive suppressor screen (Gnazzo, et al, 2017)
Our lab recently identified that the conserved RNA-Binding Protein (RBP), ATX-2, regulates cytokinesis by regulating the targeting of ZEN-4 to the spindle midzone through a conserved translation regulator, PAR-5/14-3-3sigma (Gnazzo, et al, 2016).
We have found that the anterior PAR proteins are necessary during cytokinesis (Pittman & Skop, 2012).
We published the mitotic spindle proteome (Bonner, 2011). This proteome was isolated from CHO cell mitotic spindles. The RNAi screen of the mitotic spindle proteome identifies an ER resident protein as playing a role in cytokinesis (Bonner et al, 2013).
We characterized, RACK-1, a midbody-associated protein, as playing an essential role in regulating RAB-11 endosomal trafficking during cytokinesis in the early embryo. (Ai et al, 2009). RACK-1 is also necessary for cell polarity (Ai et al, 2011).
Cell Polarity
Cell polarity is a fundamental principle underlying cellular diversity during development. In the early C. elegans embryo, polarity is established by mutually antagonistic PAR protein complexes that define distinct anterior and posterior domains. This spatial organization is reinforced by dynamic actin remodeling, which helps generate and maintain both cortical asymmetries and cytoplasmic organization. Current models propose that PAR proteins regulate membrane trafficking and recycling to establish and stabilize polarized membrane domains. However, the mechanistic links between PAR complexes, endocytic pathways, and the actin cytoskeleton remain incompletely understood. Our work focuses on identifying the molecular factors and physical mechanisms that maintain polarity within a highly dynamic and fluid membrane environment during development. By defining how polarity is established and sustained, we aim to uncover conserved principles that govern tissue organization, stem cell behavior, and developmental patterning. Disruption of these processes has broad implications, as defects in cell polarity are closely linked to developmental abnormalities and disease.
We identified Dynamin/DYN-1 as playing a necessary role in the maintenance of anterior cell polarity (Nakayama, Shivas, et al, 2009).
We have identified the Arp2/3 complex as a factor necessary for early endosome dynamics and the maintenace of PAR asymmetry (Shivas & Skop, 2012).
We have found that the anterior PAR proteins are necessary during cytokinesis (Pittman & Skop, 2012).
RACK-1 is necessary for cell polarity (Ai et al, 2011).
Cell Polarity review (Shivas, Morrison, et al, 2010)
To account for the scientific and medical profit obtained through experiments performed using HeLa cells, our lab has pledged to make donations to the Henrietta Lacks Foundation for all HeLa cell lines we created in the past and those that we create in the future. We encourage other labs to do the same. Make a donation to the Henrietta Lacks Foundation. We are indebted to Henrietta Lacks and her family for her cells that we use routinely in our lab.
Read more about Henrietta Lacks:
NYTimes Article 8-7-2003
Wikipedia
Johns Hopkins University Article
Smithsonian
The Immortal Life of Henrietta Lacks
Read more about Henrietta Lacks:
NYTimes Article 8-7-2003
Wikipedia
Johns Hopkins University Article
Smithsonian
The Immortal Life of Henrietta Lacks
