The ability to break symmetry and polarize through self-organization is a fundamental feature of cellular systems. A prevailing theory in yeast posits that symmetry breaking occurs via a positive ...feedback loop, wherein the adaptor protein Bem1 promotes local activation and accumulation of Cdc42 by directly tethering Cdc42(GTP) with its guanine nucleotide exchange factor (GEF) Cdc24. In this paper, we find that neither Bem1 nor the ability of Bem1 to bind Cdc42(GTP) is required for cell polarization. Instead, Bem1 functions primarily by boosting GEF activity, a role critical for polarization without actin filaments. In the absence of actin-based transport, polarization of Cdc42 is accomplished through Rdi1, the Cdc42 guanine nucleotide dissociation inhibitor. A mathematical model is constructed describing cell polarization as a product of distinct pathways controlling Cdc42 activation and protein localization. The model predicts a nonmonotonic dependence of cell polarization on the concentration of Rdi1 relative to that of Cdc42.
Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with ...multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance.
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•Microglial Rac1 is essential for experience-dependent brain plasticity•Rac1 modulates microglia-synapse interaction•Ablation of Rac1 in microglia hampers context-dependent learning, memory, and sociability•Increasing Rac1 signaling might improve cognitive performance in neurological disorders
Socodato et al. show that Rac1 in microglia shapes microglia-synapse interactions, synaptic plasticity, and cognition driven by experience. Loss of Rac1 in microglia disrupts synaptic architecture and impairs experience-dependent learning, memory, and sociability. The work suggests that Rac1 could be a therapeutic target in neurological disorders associated with cognitive deficits.
Tandem repeats are inherently unstable and exhibit extensive copy number polymorphisms. Despite mounting evidence for their adaptive potential, the mechanisms associated with regulation of the ...stability and copy number of tandem repeats remain largely unclear. To study copy number variation at tandem repeats, we used two well-studied repetitive arrays in the budding yeast genome, the ribosomal DNA (rDNA) locus, and the copper-inducible CUP1 gene array. We developed powerful, highly sensitive, and quantitative assays to measure repeat instability and copy number and used them in multiple high-throughput genetic screens to define pathways involved in regulating copy number variation. These screens revealed that rDNA stability and copy number are regulated by DNA replication, transcription, and histone acetylation. Through parallel studies of both arrays, we demonstrate that instability can be induced by DNA replication stress and transcription. Importantly, while changes in stability in response to stress are observed within a few cell divisions, a change in steady state repeat copy number requires selection over time. Further, H3K56 acetylation is required for regulating transcription and transcription-induced instability at the CUP1 array, and restricts transcription-induced amplification. Our work suggests that the modulation of replication and transcription is a direct, reversible strategy to alter stability at tandem repeats in response to environmental stimuli, which provides cells rapid adaptability through copy number variation. Additionally, histone acetylation may function to promote the normal adaptive program in response to transcriptional stress. Given the omnipresence of DNA replication, transcription, and chromatin marks like histone acetylation, the fundamental mechanisms we have uncovered significantly advance our understanding of the plasticity of tandem repeats more generally.
The emergent interest in artificial nanostructures that can be remotely navigated a specific location in a fluidic environment is motivated by the enormous potential this technology offers to ...biomedical applications. Originally, bio-inspired micro-/nanohelices driven by a rotating magnetic field were proposed. However, fabrication of 3D helical nanostructures is complicated. One idea to circumvent complex microfabrication is to use 1D soft magnetic nanowires that acquire chiral shape when actuated by a rotating field. The paper describes the comprehensive numerical approach for modeling propulsion of externally actuated soft magnetic nanowires. The proposed bead-spring model allows for arbitrary filament geometry and flexibility and takes rigorous account of intra-filament hydrodynamic interactions. The comparison of the numerical predictions with the previous experimental results on propulsion of composite two-segment (Ni-Ag) nanowires shows an excellent agreement. Using our model we could substantiate and rationalize important and previously unexplained details, such as bidirectional propulsion of three-segment (Ni-Ag-Au) nanowires.
Stability of axisymmetric liquid bridges Fel, Leonid G.; Rubinstein, Boris Y.
Zeitschrift für angewandte Mathematik und Physik,
12/2015, Letnik:
66, Številka:
6
Journal Article
Recenzirano
Based on the Weierstrass representation of second variation, we develop a non-spectral theory of stability for isoperimetric problem with minimized and constrained two-dimensional functionals of ...general type and free endpoints allowed to move along two given planar curves. We establish the stability criterion and apply this theory to the axisymmetric liquid bridge between two axisymmetric solid bodies without gravity to determine the stability of menisci with free contact lines. For catenoid and cylinder menisci and different solid shapes, we determine the stability domain. The other menisci (unduloid, nodoid and sphere) are considered in a simple setup between two plates. We find the existence conditions of stable unduloid menisci with and without inflection points.
Multiple liquid bridges with non-smooth interfaces Fel, Leonid G.; Rubinstein, Boris Y.; Ratner, Vadim
Zeitschrift für angewandte Mathematik und Physik,
08/2016, Letnik:
67, Številka:
4
Journal Article
Recenzirano
We consider a coexistence of two axisymmetric liquid bridges LB
i
and LB
m
of two immiscible liquids
i
and
m
which are immersed in a third liquid (or gas)
e
and trapped between two smooth solid ...bodies with axisymmetric surfaces
S
1
,
S
2
and free contact lines. Evolution of liquid bridges allows two different configurations of LB
i
and LB
m
with multiple (five or three) interfaces of non-smooth shape. We formulate a variational problem with volume constraints and present its governing equations supplemented by boundary conditions. We find a universal relationship between curvature of the interfaces and discuss the Neumann triangle relations at the singular curve where all liquids meet together.
Spontaneous symmetry breaking leading to polarization of the cell is a key step initiating many morphogenetic processes. In addition to experimental studies, model-based theoretical description helps ...to understand the conditions and limitations of this process. Such description is limited usually to linear stability analysis supplied by the numerical simulations to establish the dependence of the polarization dynamics on the model parameters. Here we describe the application of a powerful weakly nonlinear analysis method to a minimalistic model characterized by the conservation of mass of the protein governing the polarization dynamics.
During plant and animal development, monolayer cell sheets display a stereotyped distribution of polygonal cell shapes. In interphase cells these shapes range from quadrilaterals to decagons, with a ...robust average of six sides per cell. In contrast, the subset of cells in mitosis exhibits a distinct distribution with an average of seven sides. It remains unclear whether this 'mitotic shift' reflects a causal relationship between increased polygonal sidedness and increased division likelihood, or alternatively, a passive effect of local proliferation on cell shape.
We use a combination of probabilistic analysis and mathematical modeling to predict the geometry of mitotic polygonal cells in a proliferating cell layer. To test these predictions experimentally, we use Flp-Out stochastic labeling in the Drosophila wing disc to induce single cell clones, and confocal imaging to quantify the polygonal topologies of these clones as a function of cellular age. For a more generic test in an idealized cell layer, we model epithelial sheet proliferation in a finite element framework, which yields a computationally robust, emergent prediction of the mitotic cell shape distribution.
Using both mathematical and experimental approaches, we show that the mitotic shift derives primarily from passive, non-autonomous effects of mitoses in neighboring cells on each cell's geometry over the course of the cell cycle. Computationally, we predict that interphase cells should passively gain sides over time, such that cells at more advanced stages of the cell cycle will tend to have a larger number of neighbors than those at earlier stages. Validating this prediction, experimental analysis of randomly labeled epithelial cells in the Drosophila wing disc demonstrates that labeled cells exhibit an age-dependent increase in polygonal sidedness. Reinforcing these data, finite element simulations of epithelial sheet proliferation demonstrate in a generic framework that passive side-gaining is sufficient to generate a mitotic shift.
Taken together, our results strongly suggest that the mitotic shift reflects a time-dependent accumulation of shared cellular interfaces over the course of the cell cycle. These results uncover fundamental constraints on the relationship between cell shape and cell division that should be general in adherent, polarized cell layers.
Injury is common in the life of organisms. Because the extent of damage cannot be predicted, injured organisms must determine how much tissue needs to be restored. Although it is known that ...amputation position affects the regeneration speed of appendages, mechanisms conveying positional information remain unclear. We investigated tissue dynamics in regenerating caudal fins of the African killifish (Nothobranchius furzeri) and found position-specific, differential spatial distribution modulation, persistence, and magnitude of proliferation. Single-cell RNA sequencing revealed a transient regeneration-activated cell state (TRACS) in the basal epidermis that is amplified to match a given amputation position and expresses components and modifiers of the extracellular matrix (ECM). Notably, CRISPR-Cas9-mediated deletion of the ECM modifier sequestosome 1 (sqstm1) increased the regenerative capacity of distal injuries, suggesting that regeneration growth rate can be uncoupled from amputation position. We propose that basal epidermis TRACS transduce positional information to the regenerating blastema by remodeling the ECM.
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•Amputation position changes tissue-wide proliferation response•Regeneration deploys transient regeneration-activated cell states•Sqstm1 slows down regenerative outgrowth in distal injuries•Prediction: positional information is transduced by ECM changes during regeneration
Biological sciences; Zoology; Molecular biology; Cell biology
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