Cortical Contraction Research Articles

Aberrant cortex contractions impact mammalian oocyte quality

The cortex controls cell shape. In mouse oocytes, the cortex thickens in an Arp2/3-complex-dependent manner, ensuring chromosome positioning and segregation. Surprisingly, we identify that mouse oocytes lacking the Arp2/3 complex undergo cortical actin remodeling upon division, followed by cortical contractions that are unprecedented in mammalian oocytes. Using genetics, imaging, and machine learning, we show that these contractions stir the cytoplasm, resulting in impaired organelle organization and activity. Oocyte capacity to avoid polyspermy is impacted, leading to a reduced female fertility. We could diminish contractions and rescue cytoplasmic anomalies. Similar contractions were observed in human oocytes collected as byproducts during IVF (in vitro fertilization) procedures. These contractions correlate with increased cytoplasmic motion, but not with defects in spindle assembly or aneuploidy in mice or humans. Our study highlights a multiscale effect connecting cortical F-actin, contractions, and cytoplasmic organization and affecting oocyte quality, with implications for female fertility.

Cortex-driven cytoplasmic flows in elongated cells: fluid mechanics and application to nuclear transport in Drosophila embryos.

The Drosophila melanogaster embryo, an elongated multi-nucleated cell, is a classical model system for eukaryotic development and morphogenesis. Recent work has shown that bulk cytoplasmic flows, driven by cortical contractions along the walls of the embryo, enable the uniform spreading of nuclei along the anterior-posterior axis necessary for proper embryonic development. Here, we propose two mathematical models to characterize cytoplasmic flows driven by tangential cortical contractions in elongated cells. Assuming Newtonian fluid flow at low Reynolds number in a spheroidal cell, we first compute the flow field exactly, thereby bypassing the need for numerical computations. We then apply our results to recent experiments on nuclear transport in cell cycles 4-6 of Drosophila embryo development. By fitting the cortical contractions in our model to measurements, we reveal that experimental cortical flows enable near-optimal axial spreading of nuclei. A second mathematical approach, applicable to general elongated cell geometries, exploits a long-wavelength approximation to produce an even simpler solution, with errors below [Formula: see text] compared with the full model. An application of this long-wavelength result to transport leads to fully analytical solutions for the nuclear concentration that capture the essential physics of the system, including optimal axial spreading of nuclei.

Comparing amplitudes of transcranial direct current stimulation (tDCS) to the sensorimotor cortex during swallowing.

Transcranial direct current stimulation (tDCS) can alter cortical excitability, making it a useful tool for promoting neuroplasticity in dysphagia rehabilitation. Clinical trials show functional improvements in swallowing following anodal tDCS despite varying dosing parameters and outcomes. The aim of the current study was to determine the most effective amplitude criterion (e.g., 0mA [sham/control], 1mA, 2mA) of anodal tDCS for upregulating the swallowing sensorimotor cortex. As a novel paradigm, tDCS, functional near-infrared spectroscopy (fNIRS), and surface electromyography (sEMG) were simultaneously administered while participants completed a swallowing task. This allowed for measurement of the cortical hemodynamic response and submental muscle contraction before, during, and after tDCS. At the conclusion of the study, participants were asked to rate their level of discomfort associated with tDCS using a visual analog scale. There was no significant difference in the hemodynamic response by time or amplitude. However, post-hoc analyses indicated that in the post-stimulation period, changes to the hemodynamic response in the left (stimulated) hemisphere were significantly different for the groups receiving 1mA and 2mA of tDCS compared to baseline. Participants receiving 1mA of tDCS demonstrated reduced hemodynamic response. There was no significant difference in submental muscle contraction during or after tDCS regardless of amplitude. Anodal tDCS was well tolerated in healthy adults with no difference among participant discomfort scores across tDCS amplitude. During a swallowing task, healthy volunteers receiving 1mA of anodal tDCS demonstrated a suppressed hemodynamic response during and after stimulation whereas those receiving 2mA of anodal tDCS had an increase in the hemodynamic response. tDCS remains a promising tool in dysphagia rehabilitation, but dosing parameters require further clarification.

Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis

The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.

Profesor Andrzej Grębecki (1934-2021) - badacz fizjologii ruchu komórek, nauczyciel, wychowawca

14 stycznia 2021 r. po długiej chorobie odszedł profesor Andrzej Grębecki wybitny biolog komórki, zasłużony dla nauki w Polsce i na świecie, nauczyciel i wychowawca. Profesor Andrzej Grębecki ukończył Wydział Matematyczno-Przyrodniczy Uniwersytetu Łódzkiego w 1952 r., a w 1956 r. obronił pracę doktorską pod kierunkiem prof. Jana Dembowskiego. Profesor Grębecki przez wiele lat (1973-2002) kierował Pracownią Morfodynamiki Prostych Systemów Ruchowych w Zakładzie Biologii Komórki, Instytutu Nenckiego PAN. Ponadto aktywnie uczestniczył w życiu Instytutu, w którym m.in. pełnił funkcję zastępcy dyrektora d/s naukowych (1975-1981) oraz kierownika studium doktoranckiego (1975-1979). Przez dwie kadencje w latach 1984-1989 był przewodniczącym Rady Naukowej Instytutu Nenckiego. Profesor Grębecki w latach 1984-1989 był członkiem Rady Polskiej Sieci Biologii Komórkowej i Molekularnej UNESCO, a 1993-1997 członkiem International Commission of Protozoology. Zainteresowania naukowe profesora Grębeckiego skupiały się na badaniu mechanizmów ruchu komórek. Był On autorem ponad 160 opublikowanych pozycji naukowych, obejmujących pierwsze w literaturze prace o roli wapnia w regulacji ruchu rzęskowego. Następnie swoje zainteresowania naukowe profesor Grębecki skupił na badaniach fizjologii ruchu amebowego, których wyniki publikował w bardzo prestiżowych czasopismach międzynarodowych: m.in. Journal of Cell Science, European Journal of Cell Biology, Cell Biology International Reports. Główne założenia dotyczące teorii ogólnego skurczu kortykalnego zawarł w obszernej monografii ?Membrane and cytoskeleton flow in motile cells with emphasis on the contribution of free-living Amoebae?, opublikowanej w International Review of Cytology (1994). Dowodem międzynarodowego uznania dorobku profesora Grębeckiego było jego członkostwo w pracy komitetów redakcyjnych międzynarodowych czasopism naukowych: Acta Protozool. (Warszawa), Eur.J.Protistol. (Stuttgart) i Protistology (Omsk). Za swoje osiągnięcia naukowe i organizacyjne był wielokrotnie nagradzany wyróżnieniami i odznaczeniami państwowymi (m.in. Krzyż Oficerski Orderu Odrodzenia Polski - 1998).

Nuclear Deformation Lets Cells Gauge Their Physical Confinement.

How cells sense their physical microenvironment remains incompletely understood. In two recent Science articles, Lomakin etal. (2020) and Venturini etal. (2020) demonstrate that progressive nuclear deformation associated with cellular confinement triggers intracellular events that promote cell contractility and migration, revealing the nucleus to serve as a central mechanosensor.

Computational estimates of mechanical constraints on cell migration through the extracellular matrix.

Cell migration through a three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. By using computer simulations of the cell's mid-plane, we investigate two such migration mechanisms-'push-pull' (forming a finger-like protrusion, adhering to an ECM node, and pulling the cell body forward) and 'rear-squeezing' (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm, and nucleoplasm. We find that relations between three mechanical parameters-the cortex's contractile force, nuclear elasticity, and ECM rigidity-determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulation results show that nuclear stiffness limits the cell migration more than the ECM rigidity. Simulations show the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values. Additionally, results show that the rear-squeezing mechanism is aided by hydrodynamics through a pressure gradient.

Cortical contraction drives the 3D patterning of epithelial cell surfaces.

Cellular protrusions create complex cell surface topographies, but biomechanical mechanisms regulating their formation and arrangement are largely unknown. To study how protrusions form, we focused on the morphogenesis of microridges, elongated actin-based structures that are arranged in maze-like patterns on the apical surfaces of zebrafish skin cells. Microridges form by accreting simple finger-like precursors. Live imaging demonstrated that microridge morphogenesis is linked to apical constriction. A nonmuscle myosin II (NMII) reporter revealed pulsatile contractions of the actomyosin cortex, and inhibiting NMII blocked apical constriction and microridge formation. A biomechanical model suggested that contraction reduces surface tension to permit the fusion of precursors into microridges. Indeed, reducing surface tension with hyperosmolar media promoted microridge formation. In anisotropically stretched cells, microridges formed by precursor fusion along the stretch axis, which computational modeling explained as a consequence of stretch-induced cortical flow. Collectively, our results demonstrate how contraction within the 2D plane of the cortex can pattern 3D cell surfaces.

Centrosome Aurora A regulates RhoGEF ECT-2 localisation and ensures a single PAR-2 polarity axis in C. elegans embryos.

Proper establishment of cell polarity is essential for development. In the one-cell C. elegans embryo, a centrosome-localised signal provides spatial information for polarity establishment. It is hypothesised that this signal causes local inhibition of the cortical actomyosin network, and breaks symmetry to direct partitioning of the PAR proteins. However, the molecular nature of the centrosomal signal that triggers cortical anisotropy in the actomyosin network to promote polarity establishment remains elusive. Here, we discover that depletion of Aurora A kinase (AIR-1 in C. elegans) causes pronounced cortical contractions on the embryo surface, and this creates more than one PAR-2 polarity axis. This function of AIR-1 appears to be independent of its role in microtubule nucleation. Importantly, upon AIR-1 depletion, centrosome positioning becomes dispensable in dictating the PAR-2 axis. Moreover, we uncovered that a Rho GEF, ECT-2, acts downstream of AIR-1 in regulating contractility and PAR-2 localisation, and, notably, AIR-1 depletion influences ECT-2 cortical localisation. Overall, this study provides a novel insight into how an evolutionarily conserved centrosome Aurora A kinase inhibits promiscuous PAR-2 domain formation to ensure singularity in the polarity establishment axis.

Cytoplasmic flows in starfish oocytes are fully determined by cortical contractions.

Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, such as oocytes and eggs in early animal development. Here we show that cytoplasmic flows in starfish oocytes, which can be imaged well with transmission light microscopy, are fully determined by the cortical dynamics during surface contraction waves. We first show that the dynamics of the oocyte surface is highly symmetric around the animal-vegetal axis. We then mathematically solve the Stokes equation for flows inside a deforming sphere using the measured surface displacements as boundary conditions. Our theoretical predictions agree very well with the intracellular flows quantified by particle image velocimetry, proving that during this stage the starfish cytoplasm behaves as a simple Newtonian fluid on the micrometer scale. We calculate the pressure field inside the oocyte and find that its gradient is too small as to explain polar body extrusion, in contrast to earlier suggestions. Myosin II inhibition by blebbistatin confirms this conclusion, because it diminishes cell shape changes and hydrodynamic flow, but does not abolish polar body formation.

Myosin II promotes the anisotropic loss of the apical domain during Drosophila neuroblast ingression.

Epithelial-mesenchymal transitions play key roles in development and cancer and entail the loss of epithelial polarity and cell adhesion. In this study, we use quantitative live imaging of ingressing neuroblasts (NBs) in Drosophila melanogaster embryos to assess apical domain loss and junctional disassembly. Ingression is independent of the Snail family of transcriptional repressors and down-regulation of Drosophila E-cadherin (DEcad) transcription. Instead, the posttranscriptionally regulated decrease in DEcad coincides with the reduction of cell contact length and depends on tension anisotropy between NBs and their neighbors. A major driver of apical constriction and junctional disassembly are periodic pulses of junctional and medial myosin II that result in progressively stronger cortical contractions during ingression. Effective contractions require the molecular coupling between myosin and junctions and apical relaxation of neighboring cells. Moreover, planar polarization of myosin leads to the loss of anterior-posterior junctions before the loss of dorsal-ventral junctions. We conclude that planar-polarized dynamic actomyosin networks drive apical constriction and the anisotropic loss of cell contacts during NB ingression.

Cell Blebbing in Confined Microfluidic Environments.

Migrating cells can extend their leading edge by forming myosin-driven blebs and F-actin-driven pseudopods. When coerced to migrate in resistive environments, Dictyostelium cells switch from using predominately pseudopods to blebs. Bleb formation has been shown to be chemotactic and can be influenced by the direction of the chemotactic gradient. In this study, we determine the blebbing responses of developed cells of Dictyostelium discoideum to cAMP gradients of varying steepness produced in microfluidic channels with different confining heights, ranging between 1.7 μm and 3.8 μm. We show that microfluidic confinement height, gradient steepness, buffer osmolarity and Myosin II activity are important factors in determining whether cells migrate with blebs or with pseudopods. Dictyostelium cells were observed migrating within the confines of microfluidic gradient channels. When the cAMP gradient steepness is increased from 0.7 nM/μm to 20 nM/μm, cells switch from moving with a mixture of blebs and pseudopods to moving only using blebs when chemotaxing in channels with confinement heights less than 2.4 μm. Furthermore, the size of the blebs increases with gradient steepness and correlates with increases in myosin-II localization at the cell cortex. Reduction of intracellular pressure by high osmolarity buffer or inhibition of myosin-II by blebbistatin leads to a decrease in bleb formation and bleb size. Together, our data reveal that the protrusion type formed by migrating cells can be influenced by the channel height and the steepness of the cAMP gradient, and suggests that a combination of confinement-induced myosin-II localization and cAMP-regulated cortical contraction leads to increased intracellular fluid pressure and bleb formation.

Regulation of Actomyosin Contractility in Non-Muscle Cells

Actomyosin contractility in non-muscle cells is involved in numerous essential processes, including maintenance of cell architecture, environmental sensing, migration, trafficking, polarization, and cytokinesis, to name but a few. An extensive network of structural and regulatory proteins is collectively responsible for the generation of actomyosin contractility forces in the appropriate time and location within the cell to facilitate these processes. We recently mined the literature and protein databases to define this network, which we termed the Contractome (J Cell Sci. 2015 Jun 15;128(12):2209-17), with 100 proteins and over 230 interactions. A systems level analysis of the Contractome highlights key regulatory pathways involved in the assembly and activation of diverse actomyosin structures.Regulation of actin and myosin structures at the molecular level can have effects on cell level dynamics. This is exemplified by the evolutionarily conserved F-actin bundling protein plastin (a.k.a. fimbrin), which we show to be essential for polarization and cytokinesis of the C. elegans zygote. PLST-1 decorates all F-actin structures in the zygote cortex. In a mutant that abrogates the bundling activity of PLST-1, myosin foci in the cortex are distinctly smaller than in the wild-type, and while cortical contractions still occur over short distances, there is a lack of coordination in the contractile network over large length scales. This results in a substantial reduction in anterior directed cortical flow, which leads to defects in the establishment of polarity. PLST-1 is also required for cell division, as loss of PLST-1 function results in a significant delay or complete failure in cytokinesis. Thus, interlinking of the cortical network by plastin allows forces to be transmitted at a much longer length scale, facilitating the integration of local contractile events throughout the meshwork into the effective cortical forces necessary for polarity establishment and cell division.

Cortical Contraction Waves at Cytokinesis of Large Cells

Regulated changes in cortical contractility drive cytokinesis in all animal cells. In small somatic cells this regulation is dominated by microtubules: the spindle midzone positions the cytokinetic ring, while astral microtubules induce polar relaxation. However, in specialized cell types, such as oocytes, the microtubule spindle is very small relative to the cell volume and astral microtubules are very short, if present at all. Therefore, the cytokinetic signal must be transmitted to large parts of the cortex by an alternative mechanism.In these oocytes cortical contraction waves present a specialized form of cytokinetic cortical response. As expected due to the extreme difference in cell size and spindle size, our experiments show that these contraction waves are independent of microtubules. Therefore, we asked how cytokinetic signals are transduced, independent of microtubules, to the cortex.By quantifying surface curvature changes combined with imaging of fluorescent markers and inhibitor treatments, we find that the contraction wave is a band of flattening that moves across the cell driven by non-muscle myosin II (NMY2). We further find that the underlying localisation of NMY2 to the cortex is controlled by the conserved signalling module RhoA-RhoK-NMY2, which also controls contraction in the cytokinetic ring. Importantly, we find that the key cell cycle kinase, cdk1/cyclinB forms a spatial gradient across the oocyte, the low point of which sets the starting point of the contraction wave. Combining our quantitative observations with a mathematical model, we show that the spatial cdk1/cyclinB gradient combined with feedback mechanisms inherent in the RhoA-NMY2 signalling network is sufficient to explain the surface contractions. Taken together, we present a molecular-level model for surface contraction waves that identifies a conserved signalling module capable of transducing spatially and temporally organized cytokinetic signals to the cortex.

Calcium signaling and meiotic exit at fertilization in Xenopus egg.

Calcium is a universal messenger that mediates egg activation at fertilization in all sexually reproducing species studied. However, signaling pathways leading to calcium generation and the mechanisms of calcium-induced exit from meiotic arrest vary substantially among species. Here, we review the pathways of calcium signaling and the mechanisms of meiotic exit at fertilization in the eggs of the established developmental model, African clawed frog, Xenopus laevis. We also discuss calcium involvement in the early fertilization-induced events in Xenopus egg, such as membrane depolarization, the increase in intracellular pH, cortical granule exocytosis, cortical contraction, contraction wave, cortical rotation, reformation of the nuclear envelope, sperm chromatin decondensation and sister chromatid segregation.

Bacterial Cell Division: A Swirling Ring to Rule Them All?

FtsZ, a tubulin homologue and the major constituent of the bacterial Z ring, hasbeen shown to assemble into curved filament bundles, which exhibit GTP-hydrolysis-dependent turnover. Surprisingly, the presence of its membrane adaptor FtsA renders this turnover directional, inducing treadmilling and collective circular motion of filaments invitro.

A New Model System to Explore the Mechanisms and Functions of Global Cortical Contraction Waves in Oocyte and Embryo Cell Divisions

Cortical contractions are observable in cell divisions in many species, from meiotic divisions in Ascidian and starfish eggs to the early mitotic divisions of the Xenopus embryo. There have been many hypotheses concerning the function of these contractions, from generating pressure gradients to localizing mRNAs. Importantly, the physical and molecular mechanisms underlying these global contractions remain unknown, but would be essential in providing insights into their functions.As a system well-suited for live imaging and physical manipulations, we are studying the prominent contraction that occurs at the highly asymmetric meiotic division in starfish oocytes. In this system, the contraction occurs immediately before the division but its importance for the division remains controversial. Therefore, we set out to understand the molecular details and mechanics of the cortical contraction.Detailed analysis of the oocytes' shape and cytoplasmic flows revealed that the contraction wave is a flattening of the cell cortex which progresses across the whole oocyte towards the site of division with increasing intensity. This results in a strong and varied cytoplasmic flow. Visualizing the localization of components of the cytoskeleton indicates that F-actin and non-muscle myosin II are recruited to the cortical area currently undergoing contraction.To test the involvement of myosin II in the contraction, we applied the myosin II inhibitor blebbistatin that strongly hindered the contraction wave. Our analysis of the inhibition phenotype will reveal important details of the mechanisms of the contraction wave and allow us to determine the contraction waves' function. We will search for additional factors controlling the contraction wave for which an important clue is that changing the nuclear position prior to contraction repositions the axis of contraction, suggesting the involvement of nuclear factors.

A Quantitative Comparison of Human HT-1080 Fibrosarcoma Cells and Primary Human Dermal Fibroblasts Identifies a 3D Migration Mechanism with Properties Unique to the Transformed Phenotype

Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s) and primary human dermal fibroblasts (hDFs) with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM) arrays and proteolytic 3-dimensional (3D) migration was investigated using matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) (PEG) hydrogels (“synthetic extracellular matrix” or “synthetic ECM”). In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced β1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen) despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with β1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18). Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results, we propose that HT-1080s migrate in synthetic ECM with functional properties that are a direct consequence of their transformed phenotype.

The TAO kinase KIN-18 regulates contractility and establishment of polarity in the C. elegans embryo

Cell polarity is crucial for many aspects of cell and developmental biology. Cytoskeleton remodeling plays an essential role in the establishment of cell polarity. In the Caenorhabditis elegans one-cell embryo, while the actomyosin cytoskeleton is required for asymmetric localization of the PAR proteins, anterior PAR proteins exert a feedback regulation on contractility. Here we identify the TAO kinase KIN-18 as a regulator of cortical contractility in the early embryo. KIN-18 negatively regulates cortical contractions in a RHO-1 dependent manner and regulates RHO-1 cortical localization. KIN-18 contributes to polarity establishment by regulating the position of the boundary between anterior and posterior PAR proteins. Although KIN-18 is involved in polarity establishment, depletion of KIN-18 restores contractions in a par-3 mutant indicating that kin-18 is epistatic to par-3. We suggest a model in which KIN-18 provides a link between the cytoskeleton remodeling and polarity machineries, uncovering a role for TAO kinases in the regulation of cell polarity.

The size, shape, and dynamics of cellular blebs

A cellular bleb grows when a portion of the cell membrane detaches from the underlying cortex under the influence of a cytoplasmic pressure. We develop a quantitative model for the growth and dynamics of these objects in a simple two-dimensional setting. In particular, we first find the minimum cytoplasmic pressure and minimum unsupported membrane length for a stationary bleb to nucleate and grow as a function of the membrane-cortex adhesion. We next show how a bleb may travel around the periphery of the cell when the cytoplasmic pressure varies in space and time in a prescribed way and find that the traveling speed is governed by the speed of the pressure change induced by local cortical contraction while the shape of the traveling bleb is governed by the speed of cortical healing. Finally, we relax the assumption that the pressure change is prescribed and couple it hydrodynamically to the cortical contraction and membrane deformation. By quantifying the phase space of bleb formation and dynamics, our framework serves to delineate the range and scope of bleb-associated cell motility.