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Messi, Z.

Publications and source records attributed to Messi, Z..

4 recordsLinked to original sources

Distinct signaling center and progenitor identity dynamics initiate human forebrain patterning

At which developmental stage does the human brain start to differ from other mammals? We uncover human features of telencephalic patterning as early as the fourth post-conception week, comparing the early mouse and human forebrains using single-cell transcriptomics and 3D spatial multi-transcript imaging. In comparison to mice, the human telencephalon is delayed in ventral SHH signaling, accompanied by a human signature of anterior FGF signaling. These observations correlate with a less-resolved patterning and reduced progenitor diversity along the dorsoventral and anteroposterior axes, as well as a human early neurogenic signature. Our complementary approaches reveal a human divergence in allocation of telencephalic progenitor identities, propelled by temporal and qualitative differences in ventro-anterior signals following neural tube closure in the developing forebrain.

developmental biology↗

Cell cycle oscillations in a polarity network facilitate state switching by morphogenetic cues

The proper establishment of cell form, fate, and function during morphogenesis requires precise coordination between cell polarity and developmental cues. To achieve this, cells must establish polarity domains that are stable yet sensitive to guiding cues. Here we show that C. elegans germline blastomeres resolve this trade-off by creating a time-varying polarization landscape. Specifically, coupling the PAR polarity network to the cell-cycle kinase CDK-1 ensures that newborn cells operate in a low-feedback regime that lowers barriers to polarity state switching, allowing spatial cues to induce and orient PAR protein asymmetries. As CDK-1 activity rises at mitotic entry, increasing molecular feedback reinforces cue-induced asymmetries to yield robust and stable patterning of PAR domains. Consistent with this model, optogenetic and chemical perturbations show that low-CDK/low-feedback regimes destabilize PAR domains but are required for both de novo polarization and the reorientation of polarity in response to inductive cues. We propose that mitotic oscillations in cell polarity circuits dynamically optimize the polarization landscape to enable coordination of polarity with morphogenesis. Such temporal control of developmental networks is likely a general mechanism to balance robustness of cellular states with sensitivity to signal-induced state switching. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/681824v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@18b39f3org.highwire.dtl.DTLVardef@1898670org.highwire.dtl.DTLVardef@1d95517org.highwire.dtl.DTLVardef@1615f14_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

Balanced contractility and adhesion drive polarization in a minimal elastic actomyosin network

Polarization of migrating cells involves chemical and mechanical interactions of signaling networks, cytoskeleton, plasma membrane, and substrate adhesions. Still, it is not fully understood which mechanisms and components are sufficient for symmetry breaking, and if they work independently or together. Here, we use a discrete active network model to investigate if and how an elastic cytoskeletal network is capable of breaking symmetry solely through mechanical interactions. Our minimal model consists of elastic bonds, attractive force dipoles, and force-sensitive anchor points, initially distributed uniformly and subject to simple turnover rules. We find that these features are sufficient to produce different cell behaviors, and, remarkably, to drive symmetry breaking and directed (polarized) motion. Network behavior was primarily determined by the turnover rate of anchor points, which, itself, is a function of the ratio between dipole force and the threshold force required for anchor removal. Directional motion emerged at intermediate turnover rates, at which tension in the network accumulated through several turnover cycles before eventually exceeding the adhesion removal threshold locally at the edge, mirroring our recent experimental findings on correlation of the traction force with protrusion-retraction transitions in the cell [1, 2]. At high turnover rates, forces were unable to build up to sufficiently high levels, while at low turnover rates, anchors hinder motion. These results demonstrate how directed motion can emerge as an intrinsic property of a simple mechanical network, independently of external cues or complex signaling networks. Given the concordance between this model and recent experimental findings, we suggest that polarization by contraction-adhesion dynamics could be a fundamental emergent behavior of actin-myosin networks. Author summaryCells often need to move, for example, during development, wound healing, or immune responses. To do so, they must first decide where their "front" and "back" are, a process known as polarization. Most explanations for this behavior focus on complex chemical signaling inside the cell. In our work, we asked a simpler question: could mechanical forces within a cell be sufficient to make it polarize and move without an external cue? To explore this idea, we developed a computational model of a simplified cell made only of elastic connections, contractile forces, and attachment points to its surroundings. We started with a completely uniform system, without any built-in direction or external guidance. Surprisingly, we found that this minimal mechanical setup could spontaneously develop a front and a back and begin moving persistently. We proposed that the key mechanical factor controlling this behavior was the rate at which the attachment points break under mechanical load. When this process occurred at an intermediate rate, forces built up unevenly, leading to detachment and forward motion, similar to what is observed in-vitro. Our findings suggest that cell polarization and movement can emerge spontaneously from mechanical properties alone, highlighting an important and overlooked role for mechanics in cell behavior.

biophysics↗

Traction forces control cell-edge dynamics and mediate distance-sensitivity during cell polarization

Traction forces are generated by cellular actin-myosin system and transmitted to the environment through adhesions. They are believed to drive cell motion, shape changes, and extracellular matrix remodeling [1-3]. However, most of the traction force analysis has been performed on stationary cells, investigating forces at the level of individual focal adhesions or linking them to static cell parameters such as area and edge curvature [4-10]. It is not well understood how traction forces are related to shape changes and motion, e.g. forces were reported to either increase or drop prior to cell retraction [11-15]. Here, we analyze the dynamics of traction forces during the protrusion-retraction cycle of polarizing fish epidermal keratocytes and find that forces fluctuate in concert with the cycle, increasing during the protrusion phase and reaching maximum at the beginning of retraction. We relate force dynamics to the recently discovered phenomenological rule [16] that governs cell edge behavior during keratocyte polarization: both traction forces and the probability of switch from protrusion to retraction increase with the distance from the cell center. Diminishing traction forces with cell contractility inhibitor leads to decreased edge fluctuations and abnormal polarization, while externally applied force can induce protrusion-retraction switch. These results suggest that forces mediate distance-sensitivity of the edge dynamics and ultimately organize cell-edge behavior leading to spontaneous polarization. Actin flow rate did not exhibit the same distance-dependence as traction stress, arguing against its role in organizing edge dynamics. Finally, using a simple model of actin-myosin network, we show that force-distance relationship may be an emergent feature of such networks.

cell biology↗