Biology subjects

Stanoev, A.

Publications and source records attributed to Stanoev, A..

8 recordsLinked to original sources

bioRxiv2024

From the fly connectome to exact ring attractor dynamics

A cognitive compass enabling spatial navigation requires the neural representation of head direction (HD), yet the neural circuit architecture enabling this representation remains unclear. While various network models have been proposed to explain HD systems, these models rely on simplified circuit architectures that may be irreconcilable with empirical observations from connectomes. Here we construct a neural network model for the fruit fly HD system that satisfies both connectome-derived architectural constraints and the functional requirement of continuous head-direction representation. To achieve this, we first characterized an ensemble of continuous attractor networks where compass neurons providing local mutual excitation are coupled to inhibitory neurons. Our multipopulation model allowed us to discover a new class of ring attractor network with weaker symmetry requirements than usually assumed. For each of the four available fly connectomes, our analyses uncovered three distinct realizations of these networks. Furthermore, we found that synaptic variations among and around the fly connectomes can be compensated by cell-type-specific rescaling of synaptic weights, which could be potentially achieved through neuromodulation. The fly connectomes are ideally configured to take advantage of this mechanism, suggesting a novel design principle linking synapse-resolution connectivity to network computation.

neuroscience↗

bioRxiv2023

A rotational velocity estimate constructed through visuomotor competition updates the fly's neural compass

Navigating animals continuously integrate velocity signals to update internal representations of their directional heading and spatial location in the environment. How neural circuits combine sensory and motor information to construct these velocity estimates and how these self-motion signals, in turn, update internal representations that support navigational computations are not well understood. Recent work in Drosophila has identified a neural circuit that performs angular path integration to compute the flys head direction, but the nature of the velocity signal is unknown. Here we identify a pair of neurons necessary for angular path integration that encode the flys rotational velocity with high accuracy using both visual optic flow and motor information. This estimate of rotational velocity does not rely on a moment-to-moment integration of sensory and motor information. Rather, when visual and motor signals are congruent, these neurons prioritize motor information over visual information, and when the two signals are in conflict, reciprocal inhibition selects either the motor or visual signal. Together, our results suggest that flies update their head direction representation by constructing an estimate of rotational velocity that relies primarily on motor information and only incorporates optic flow signals in specific sensorimotor contexts, such as when the motor signal is absent.

neuroscience↗

bioRxiv2022

RPTPγ is a redox-regulated suppressor of promigratory EGFR signaling

Spatially-organized interaction dynamics between proto-oncogenic epidermal growth factor receptor (EGFR) and protein tyrosine phosphatases (PTPs) determine EGFRs phosphorylation response to growth factors and thereby cellular behavior within developing tissues. We show here, that and how the coupling between EGFR and RPTP{gamma} activity leads to migratory signaling responses to very low, physiological growth factor stimuli while suppressing aberrant, spontaneous signaling. Single cell imaging of EGFR phosphorylation and PTP oxidation revealed that RPTP{gamma} fully suppresses spontaneous EGFR phosphorylation, while EGF-induced NADPH-oxidase activity enables promigratory signaling responses at the plasma membrane by H2O2-mediated oxidative inhibition of RPTP{gamma}s phosphatase activity. The EGF-dependent toggle switch dynamics between interacting EGFR monomers and RPTP{gamma} thereby enables autocatalytically amplified phosphorylation responses to very low, physiological, EGF levels even at sparse receptor expression. This signaling mechanism is distinct from the proliferative signaling stemming from liganded endosomal EGFR complexes at high growth factor concentrations. Accordingly, RPTP{gamma} knock-out results in spontaneous promigratory EGFR signaling but loss of proliferative signaling. We thereby provide evidence of RPTP{gamma}s suppressor function of oncogenic, promigratory EGFR-signaling from the plasma membrane.

systems biology↗

bioRxiv2020

Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell fates in embryonic stem cells

During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations of multipotent precursor cells. Molecular mechanisms that enable both robust cell type proportioning despite variable initial conditions in the precursor cells, as well as the re-establishment of these proportions upon perturbations in a developing tissue remain to be characterized. Here we report that the differentiation of robust proportions of epiblast-like and primitive endoderm-like cells in mouse embryonic stem cell cultures emerges at the population level through cell-cell communication via a short-range FGF4 signal. We characterize the molecular and dynamical properties of the communication mechanism, and show how it controls both robust cell type proportioning from a wide range of experimentally controlled initial conditions, as well as the autonomous re-establishment of these proportions following the isolation of one cell type. The generation and maintenance of reproducible proportions of discrete cell types is a new function for FGF signaling that may operate in a range of developing tissues.

developmental biology↗

bioRxiv2019

Robustness and timing of cellular differentiation through population-based symmetry breaking

During mammalian development, cell types expressing mutually exclusive genetic markers are differentiated from a multilineage primed state. These observations have invoked single-cell multistability view as the dynamical basis of differentiation. However, the robust regulative nature of mammalian development is not captured therein. Considering the well-established role of cell-cell communication in this process, we propose a fundamentally different dynamical treatment in which cellular identities emerge and are maintained on population level, as a novel unique solution of the coupled system. Subcritical systems organization here enables symmetry-breaking to be triggered by cell number increase in a timed, self-organized manner. Robust cell type proportions are thereby an inherent feature of the resulting inhomogeneous solution. This framework is generic, as exemplified for early embryogenesis and neurogenesis cases. Distinct from mechanisms that rely on pre-existing asymmetries, we thus demonstrate that robustness and accuracy necessarily emerge from the cooperative behaviour of growing cell populations during development.

systems biology↗

bioRxiv2019

Optimal biochemical information processing at criticality

How cells utilize surface receptors for chemoreception is a recurrent question spanning between physics and biology over the past few decades. However, the dynamical mechanism for processing time-varying signals is still unclear. Using dynamical systems formalism to describe criticality in non-equilibrium systems, we propose generic principle for temporal information processing through phase-space trajectories using dynamic transient memory. In contrast to short-term memory, dynamic memory generated via ghost attractor enables signal integration depending on stimulus history, and thus balance between stability and plasticity in receptor responses. We propose that self-organization at criticality can arise through fluctuation-sensing mechanism, illustrated for the experimentally established epidermal growth factor sensing system. This framework applies irrespective of the intrinsic node dynamics or network size, as we show using also a basic neuronal model. Processing of non-stationary signals, a feature previously attributed only to neuronal networks, thus uniquely emerges for biochemical networks organized at criticality.

systems biology↗

bioRxiv2018

A spatially regulated GTPase cycle of Rheb controls growth factor signaling to mTORC1

Growth factors initiate anabolism by activating mechanistic target of rapamycin complex 1 (mTORC1) via the small GTPase Rheb. We show that the GTPase cycle of Rheb is spatially regulated by the interaction with its GDI-like solubilizing factor (GSF) - PDE{delta}. Arl2-GTP mediated localized release of cytosolic Rheb-GTP from PDE{delta} deposits it onto perinuclear membranes where it forms a complex with mTORC1. The membrane associated GTPase activating protein (GAP) TSC2 hydrolyzes Rheb-GTP, weakening the interaction with mTOR. Rheb-GDP is readily released into the cytosol where it is maintained soluble by interaction with PDE{delta}. This solubilized Rheb is re-activated by nucleotide exchange to be re-deposited by Arl2-mediated release onto perinuclear membranes. This spatial GTPase cycle thereby enables mTORC1 activation to be solely controlled by growth factor induced inactivation of TSC2. The coupling between mTOR activation and spatially regulated Rheb nucleotide exchange makes growth factor induced proliferation critically dependent on PDE{delta} expression.

cell biology↗

bioRxiv2018

Interdependence of EGFR with PTPs on juxtaposed membranes generates a growth factor sensing and responding network

The proto-oncogenic epidermal growth factor receptor (EGFR) is a tyrosine kinase whose sensitivity to growth factors (GFs) and signal duration determines cellular behavior. We resolve how EGFRs response to epidermal growth factor (EGF) originates from dynamically established recursive interactions with spatially organized protein tyrosine phosphatases (PTPs). Opposed genetic PTP perturbations enabled identification of receptor-like PTPRG/J at the plasma membrane (PM) and endoplasmic reticulum (ER) associated PTPN2 as the major EGFR dephosphorylating activities. Imaging spatial-temporal PTP reactivity then revealed that vesicular trafficking establishes a spatially-distributed negative feedback with PTPN2 that determines signal duration, whereas single cell dose-response analysis uncovered a ROS-mediated toggle switch between autocatalytically activated monomeric EGFR and the tumor suppressor PTPRG that governs EGFRs sensitivity to EGF. Vesicular recycling of monomeric EGFR unifies the interactions with these PTPs on juxtaposed membranes, dynamically generating a network architecture that can sense and respond to time varying growth factor signals.

systems biology↗