Biology subjects

Weber, I.

Publications and source records attributed to Weber, I..

7 recordsLinked to original sources

bioRxiv2026

IqgD is a Rac1-interacting IQGAP required for efficient growth of Dictyostelium discoideum on bacterial lawns

IQGAPs are large multidomain scaffold proteins that interact with the Rho family GTPases Cdc42 and Rac1, functioning both as their effectors and as regulators by stabilizing their active GTP-bound state. In this study, we analyzed the function of IqgD, an IQGAP-related protein from the professional phagocyte Dictyostelium discoideum. IqgD contains a calponin homology domain (CHD), a GAP-related domain (GRD), and a RasGAP C-terminal (RGCt) domain. We show that the CHD is essential for F-actin binding and cortical localization, whereas the GRD and RGCt domains mediate interactions with Rac1 GTPases and the actin-bundling proteins cortexillins. Moreover, similar to mammalian IQGAPs, IqgD maintains Rac1 in its active conformation. IqgD is enriched in macropinocytic and phagocytic cups and co-localizes with F-actin and active Rac1 in the ring-like structure that forms around surface-bound particles at the cell bottom. Loss of IqgD results in markedly reduced growth on bacterial lawns and significantly smaller cell size. While mutant cells internalize bacteria from suspension as efficiently as wild-type cells, they display a strong defect in phagocytosis of surface-bound particles, accompanied by decreased adhesion to the cell substrate. Together, our data show that although IqgD localizes to macroendocytic cups, it is dispensable for macropinocytosis and phagocytosis of suspended particles. Instead, IqgD is specifically required for efficient phagocytosis of surface-bound particles, likely by facilitating robust F-actin polymerization at the cell bottom to generate the force necessary for detachment of surface-bound bacteria. Significance StatementPhagocytosis of surface-bound microbes is essential for host defense and environmental feeding strategies, yet its underlying mechanisms remain poorly understood. We identify the IQGAP-related protein IqgD in D. discoideum as a key factor required for efficient uptake of bacteria attached to solid surfaces. IqgD localizes to an F-actin- and Rac1-rich circular structure analogous to the phagocytic adhesion ring (PAR) recently described in mammalian macrophages, suggesting that this mode of force-driven particle detachment is evolutionarily conserved. Our findings provide mechanistic insight into substrate-dependent phagocytosis and establish IqgD as a central regulator of this process.

cell biology↗

bioRxiv2025

Characterizing the frequency-specific and spatiotemporal dynamics of β-γ Phase-Amplitude Coupling in Parkinson's disease

Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscillation is coupled to the phase of a slower brain oscillation, is implicated in various higher-order cognitive functions and was shown to be pathologically altered in neurological and psychiatric disease. In Parkinsons disease (PD), the coupling between gamma amplitude (50-150 Hz) to beta phase (13-35 Hz) is exaggerated. Enhanced {beta}-{gamma} PAC was found in the subthalamic nucleus and various cortical sources and shown to be responsive to dopaminergic therapy and deep brain stimulation (DBS). Therefore, exaggerated {beta}-{gamma} PAC has been proposed to be a disease marker and a potential target for brain circuit interventions. Despite these promising findings, a significant knowledge gap remains, as the spatial and frequency-specific dynamics of {beta}-{gamma} PAC and its association with motor symptoms and therapy remain elusive. To address this knowledge gap, we employed high-density electroencephalography (EEG) with advanced source localisation techniques for PD patients at rest. We highlight three key findings: (1) a frequency-specific increase in high {beta} (23-35 Hz)-{gamma} PAC within and between sources of the cortical motor network, (2) a link between elevated high {beta}-{gamma} PAC and bradykinesia and rigidity when OFF medication, but not tremor, and (3) a medication-induced reduction in high {beta}-{gamma} PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides novel insights into the pathophysiology of PD as an oscillopathy and identifies high {beta}-{gamma} PAC as a potential marker of Parkinsonian symptoms and treatment effects. This has important implications for invasive as well as non-invasive therapeutic strategies as high {beta}-{gamma} PAC targeting might hold greater promise than targeting {beta}-{gamma} PAC per se.

neuroscience↗

bioRxiv2024

The IQGAP-related RasGAP IqgC regulates cell-substratum adhesion in Dictyostelium discoideum

Proper adhesion of cells to their environment is essential for the normal functioning of single cells and multicellular organisms. To attach to the extracellular matrix (ECM), mammalian cells form integrin adhesion complexes consisting of many proteins that together link the ECM and the actin cytoskeleton. Similar to mammalian cells, the amoeboid cells of the protist Dictyostelium discoideum also use multiprotein adhesion complexes to control their attachment to the underlying surface. However, the exact composition of the multiprotein complexes and the signaling pathways involved in the regulation of adhesion in D. discoideum have not yet been elucidated. Here we show that the IQGAP-related protein IqgC is important for normal attachment of D. discoideum cells to the substratum. Mutant iqgC-null cells have impaired adhesion, whereas overexpression of IqgC promotes directional migration. A RasGAP C-terminal (RGCt) domain of IqgC is sufficient for its localization in the ventral adhesion focal complexes, while RasGAP activity of a GAP-related domain (GRD) is additionally required for the proper function of IqgC in adhesion. We identify the small GTPase RapA as a novel direct IqgC interactor and show that IqgC participates in a RapA-regulated signaling pathway targeting the adhesion complexes that include talin A, myosin VII and paxillin B. Based on our results, we propose that IqgC is a positive regulator of adhesion, responsible for the strengthening of ventral adhesion structures and for the temporal control of their subsequent degradation.

cell biology↗

bioRxiv2024

Oscillatory dynamics of Rac1 activity in Dictyostelium discoideum amoebae

Small GTPases of the Rho family play a central role in the regulation of cell motility by controlling the remodeling of the actin cytoskeleton. In the amoeboid cells of Dictyostelium discoideum, the active form of the Rho GTPase Rac1 regulates actin polymerases at the leading edge and actin filament bundling proteins at the posterior cortex of polarized cells. However, constitutive Rac1 dynamics in D. discoideum have not yet been systematically investigated. Therefore, we monitored the spatiotemporal dynamics of Rac1 activity in vegetative amoebae using a specific fluorescent probe. We observed that plasma membrane domains enriched in active Rac1 not only exhibited stable polarization, but also showed rotations and oscillations. To simulate the observed dynamics, we developed a mass-conserving reaction-diffusion model based on the circulation of Rac1 between the membrane and the cytoplasm in conjunction with its activation by GEFs, deactivation by GAPs and interaction with the Rac1 effector DGAP1. Our theoretical model accurately reproduced the experimentally observed dynamic patterns, including the predominant anti-correlation between active Rac1 and DGAP1. Significantly, the model predicted a new colocalization regime of these two proteins in polarized cells, which we confirmed experimentally. In summary, our results improve the understanding of Rac1 dynamics and reveal how the occurrence and transitions between different regimes depend on biochemical reaction rates, protein levels and cell size. This study not only expands our knowledge of the behavior of small GTPases in D. discoideum amoebae, but also provides a simple modeling framework that can be adapted to study similar dynamics in other cell types.

systems biology↗

bioRxiv2022

Predicting Anti-Cancer Drug Combination Responses with a Temporal Cell State Network Model

Cancer chemotherapy combines multiple drugs, but predicting the effects of drug combinations on cancer cell proliferation remains challenging. We hypothesized that by combining knowledge of single drug dose responses and cell state transition network dynamics, we could predict how a population of cancer cells will respond to drug combinations. We tested this hypothesis here using three targeted inhibitors of different cell cycle states in two different cell lines. We formulated a Markov model to capture temporal cell state transitions between different cell cycle phases, with single drug data constraining how drug doses affect transition rates. This model was able to predict the landscape of all three different pairwise drug combinations across all dose ranges for both cell lines with no additional data. This work shows how currently available or attainable information could be combined to predict how cancer cell populations respond to drug combinations.

systems biology↗

bioRxiv2021

A waveform-independent measure of recurrent neural activity

Rhythmic neural activity, so called oscillations, play a key role for neural information transmission, processing and storage. Neural oscillations in distinct frequency bands are central to physiological brain function and alterations thereof have been associated with several neurological and psychiatric disorders. The most common methods to analyse neural oscillations, e.g. short-term Fourier transform or wavelet analysis, assume that measured neural activity is composed of a series of symmetric prototypical waveforms, e.g. sinusoids. However, usually the models generating the signal, including waveform shapes of experimentally measured neural activity are unknown. Decomposing asymmetric waveforms of nonlinear origin using these classic methods may result in spurious harmonics visible in the estimated frequency spectra. Here, we introduce a new method for capturing rhythmic brain activity based on recurrences of similar states in phase-space. This method allows for a time-resolved estimation of amplitude fluctuations of recurrent activity irrespective of or specific to waveform-shapes. The algorithm is derived from the well-established field of recurrence analysis, which has rarely been adopted in neuroscience. In this paper, we show its advantages and limitations in comparison to short-time Fourier transform and wavelet convolution using periodic signals of different waveform shapes. Further, we demonstrate its application using experimental data, i.e. intracranial electrophysiological recordings from the human motor cortex of one epilepsy patient.

bioinformatics↗

bioRxiv2020

Increased prefrontal top-down control in older adults predicts motor performance and age-group association

Bimanual motor control declines during ageing, affecting the ability of older adults to maintain independence. An important underlying factor is cortical atrophy, particularly affecting frontal and parietal areas in older adults. As these regions and their interplay are highly involved in bimanual motor preparation, we investigated age-related connectivity changes between prefrontal and premotor areas of young and older adults during the preparatory phase of complex bimanual movements using high-density electroencephalography. Generative modelling showed that excitatory interhemispheric prefrontal to premotor coupling in older adults predicted age-group affiliation and was associated with poor motor-performance. In contrast, excitatory intrahemispheric prefrontal to premotor coupling enabled older adults to maintain motor-performance at the cost of lower movement speed. Our results disentangle the complex interplay in the prefrontal-premotor network during movement preparation underlying reduced bimanual control and the well-known speed-accuracy trade-off seen in older adults.

neuroscience↗