Rho Flares Repair Local Tight Junction Leaks

Stephenson, Rachel E.; Higashi, Tomohito; Erofeev, Ivan; Arnold, Torey R.; Leda, Marcin; Goryachev, Andrew B.; Miller, Ann L.

doi:10.1016/j.devcel.2019.01.016

Cited by 88 publications

(136 citation statements)

References 66 publications

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“…Since these analyses assumed a constant pore length without any independent measurements, these conclusions must be regarded as tentative. We have observed that treatment of MDCK Type II renal epithelial cells with hydrogen peroxide, which increases Leak Pathway permeability, also increases cell twisting and movement (data not shown), similar to the effects of cell division described by Stephenson et al [125]. In this context, it is interesting to note the marked parallels between regulation of tight junction and adherens junction integrity.…”

Section: What Is the Leak Pathway?supporting

confidence: 83%

“…It is likely that these localized regions may not exist on every cell at any single time point. Two recent studies demonstrating a small number of discrete sites where macromolecules cross the tight junction lend strong support for this concept of the Leak Pathway [124,125]. Stephenson et al [125] reported that sites of solute permeation were transient, remaining open for no more than 5 minutes.…”

Section: What Is the Leak Pathway?mentioning

confidence: 96%

“…Two recent studies demonstrating a small number of discrete sites where macromolecules cross the tight junction lend strong support for this concept of the Leak Pathway [124,125]. Stephenson et al [125] reported that sites of solute permeation were transient, remaining open for no more than 5 minutes. Richter et al [124] also reported that macromolecule permeability at some sites was transient, being "open" for 30 minutes or less.…”

Section: What Is the Leak Pathway?mentioning

confidence: 96%

“…A recent report may provide some insight into the molecular basis for the Leak Pathway and how it may be regulated. Stephenson et al [125] studied the maintenance of tight junctions in the embryonic epithelium of the Xenopus laevis embryo. They demonstrated that localized disruptions of the tight junction occurred at sites of increased tension caused by junction elongation as cells in the embryo divided.…”

Section: What Is the Leak Pathway?mentioning

confidence: 99%

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The Leak Pathway: A Pathway in Flux

Monaco¹,

Ovryn²,

Axis³

et al. 2019

Preprint

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The epithelial cell tight junction structure is the site of the transepithelial movement of solutes and water between epithelial cells (paracellular permeability). Paracellular permeability can be divided into two distinct pathways, the Pore Pathway mediating the movement of small ions and solutes and the Leak Pathway mediating the movement of large solutes. Claudin proteins form the basic paracellular permeability barrier and mediate the movement of small ions and solutes via the Pore Pathway. The Leak Pathway remains less understood. Several proteins have been implicated in mediating the Leak Pathway, including occludin, ZO proteins, tricellulin, and actin filaments, but the proteins comprising the Leak Pathway remain unresolved. The properties of the Leak Pathway, such as its molecular mechanism, its regulation, and whether or not it has a potential size limit, remain controversial. This review will trace the evolution of the Leak Pathway concept from its origins, will discuss the current information about the properties of the Leak Pathway, and will discuss recent research suggesting a possible molecular basis for the Leak Pathway. Based on these findings, we propose a model for the molecular mechanism underlying the Leak Pathway and its regulation.

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Section: What Is the Leak Pathway?supporting

confidence: 83%

Section: What Is the Leak Pathway?mentioning

confidence: 96%

Section: What Is the Leak Pathway?mentioning

confidence: 96%

Section: What Is the Leak Pathway?mentioning

confidence: 99%

See 2 more Smart Citations

The Leak Pathway: A Pathway in Flux

Monaco¹,

Ovryn²,

Axis³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…As mentioned already, a hot spot to generate membrane protrusion was multicellular junctions where multiple bicellular junctions meet ( Fig. 2D), and the multicellular junctions are thought to be prone to disruption, as they receive tensile force from the bicellular junctions (Higashi and Miller, 2017;Stephenson et al, 2019). Such force is generated by contraction of junction-associated actomyosin, and therefore we examined whether there is any relation between myosin II activation and clamellipodia formation.…”

Section: Aj Disruption Induces Myosin II Activationmentioning

confidence: 93%

Adherens junction serves to generate cryptic lamellipodia required for collective migration of epithelial cells

Ozawa

Hiver

Yamamoto

et al. 2020

Preprint

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Collective migration of epithelial cells plays crucial roles in various biological processes such as cancer invasion. In migrating epithelial sheets, leader cells form lamellipodia to advance, and follower cells also form similar motile apparatus at cell-cell boundaries, which are called cryptic lamellipodia (c-lamellipodia). Using adenocarcinoma-derived epithelial cells, we investigated how c-lamellipodia are generated, and found that they sporadically grew from Ecadherin-based adherens junctions (AJs). WAVE and Arp2/3 complexes were localized along the AJs, and silencing them not only interfered with c-lamellipodia formation but also prevented follower cells from trailing the leaders. Disruption of AJs by removing aE-catenin resulted in uncontrolled c-lamellipodia growth, and this was brought about by myosin II activation and the resultant contraction of AJ-associated actomyosin cables. Additional observations indicated that c-lamellipodia tended to grow at mechanically weak sites of the junction. We conclude that AJs not only tie cells together but also generate c-lamellipodia by recruiting actin regulators, enabling epithelial cells to undergo ordered collective migration.

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The Heterotaxy Gene CCDC11 Is Important for Cytokinesis via RhoA Regulation

Kulkarni,

Stephenson,

Amalraj

et al. 2024

Cytoskeleton

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Mutations in CCDC11 (cfap53) have been identified in multiple patients with heterotaxy (Htx), a disorder of left–right (LR) patterning of the internal organs. In Xenopus, depletion of Ccdc11 causes defects in LR patterning, recapitulating the patient phenotype. Upon Ccdc11 depletion, monociliated cells of the Left–Right Organizer (LRO) exhibit multiple cilia per cell. Unexpectedly, we found that Ccdc11 is necessary for successful cytokinesis, explaining the multiciliation phenotype observed in Ccdc11‐depleted cells. The small GTPase RhoA is critical for cytokinesis, and our Ccdc11 depletion phenotypes are reminiscent of RhoA loss of function. Here, we demonstrate that during cytokinesis CCDC11 is localized to the cytokinetic contractile ring overlapping with RhoA, and CCDC11 regulates total RhoA protein levels. Our results connect CCDC11 to cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for heterotaxy disease pathogenesis.

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Rho Flares Repair Local Tight Junction Leaks

Cited by 88 publications

References 66 publications

The Leak Pathway: A Pathway in Flux

The Leak Pathway: A Pathway in Flux

Adherens junction serves to generate cryptic lamellipodia required for collective migration of epithelial cells

The Heterotaxy Gene CCDC11 Is Important for Cytokinesis via RhoA Regulation

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