Biology subjects

Oozeer, F.

Publications and source records attributed to Oozeer, F..

7 recordsLinked to original sources

bioRxiv2025

Structural mechanisms of drebrin-mediated F-actin network modulation

Drebrin modulates F-actin networks and links them to other intracellular components, regulating crucial processes including neuritogenesis, synaptic plasticity, virus internalisation and cancer invasion. Using single-particle cryo-EM we characterise drebrins interaction with F-actin through two separate conserved actin binding domains (ABD1 and ABD2), revealing structural bases for its F-actin-modulating properties. We describe a multimodal interaction where drebrins ABD1 can adopt two conformations and a long flexible loop connecting to ABD2 allows the two ABDs to occupy multiple relative positions along F-actin. Despite harbouring two separated ABDs, we find that drebrin is not a strong direct F-actin bundler. Drebrins ABDs bind across multiple actin protomers and their subdomains and modify the longitudinal inter-protomer interface, explaining their F-actin stabilising properties. Furthermore, we show drebrins binding site on F-actin is shared with other critical actin-binding and regulatory proteins, explaining their competitive displacement.

biochemistry↗

bioRxiv2024

A postnatal molecular switch drives the activity-dependent maturation of parvalbumin interneurons

Cortical neurons are specified during embryonic development but often only acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1). Developmental loss of PGC-1 prevents PV+ interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1 exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERR{gamma} and Mef2c. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program promoting the maturation of PV+ interneurons at the appropriate developmental stage.

neuroscience↗

bioRxiv2023

Somatostatin interneurons control the timing of developmental desynchronization in cortical networks

Synchronous neuronal activity is a hallmark of the early developing brain. In the mouse cerebral cortex, activity decorrelates during the second week of postnatal development, progressively acquiring the characteristic pattern of sparse coding underlying the integration of multidimensional sensory information. The maturation of inhibition seems critical for this process, but the specific types of interneurons involved in this crucial transition of network activity in the developing cortex remain unknown. Using in vivo volumetric and longitudinal two-photon calcium imaging during the period that precedes the change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) interneurons as critical modulators of this switch. Modulation of the activity of SST+ cells accelerates or delays the decorrelation of cortical network activity, a process that involves regulating the degree of maturation of parvalbumin-expressing (PV+) interneurons. SST+ cells critically link sensory inputs with local circuits controlling the neural dynamics in the developing cortex while modulating the integration of other interneurons into nascent cortical circuits.

neuroscience↗

bioRxiv2023

Regulation of parvalbumin interneuron plasticity by neuropeptide-encoding genes

Neuronal activity is regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity, for example, during learning, might disturb this balance, eliciting compensatory mechanisms to maintain network function. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilising plasticity. However, while neuronal plasticity has been thoroughly studied in pyramidal cells, little is known about how interneurons adapt to persistent changes in their activity. Here we uncover the critical cellular and molecular mechanisms through which cortical parvalbumin-expressing (PV+) interneurons adapt to changes in their activity levels. We found that changes in the activity of PV+ interneurons drive cell-autonomous, bi-directional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV+ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of PV+ interneurons leads to the cell-autonomous upregulation of two genes encoding multiple secreted neuropeptides, Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV+ synapses onto PV+ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV+ interneurons in the adult mouse neocortex.

neuroscience↗

bioRxiv2021

Input-specific control of interneuron numbers in nascent striatal networks

The assembly of functional neuronal circuits requires appropriate numbers of distinct classes of neurons, but the mechanisms through which their relative proportions are established remain poorly defined. Investigating the mouse striatum, here we found that the two most prominent subtypes of striatal interneurons, parvalbumin-expressing (PV+) GABAergic and cholinergic (ChAT+) interneurons, undergo extensive programmed cell death between the first and second postnatal weeks. Remarkably, the survival of PV+ and ChAT+ interneurons is regulated by distinct mechanisms mediated by their specific afferent connectivity. While long-range cortical inputs control PV+ interneuron survival, ChAT+ interneuron survival is regulated by local input from the medium spiny neurons. Our results identify input-specific circuit mechanisms that operate during the period of programmed cell death to establish the final number of interneurons in nascent striatal networks.

neuroscience↗

bioRxiv2021

Cortical wiring by synapse-specific control of local protein synthesis

Neurons use local protein synthesis as a mechanism to support their morphological complexity, which requires independent control across multiple subcellular compartments including individual synapses. However, to what extent local translation is differentially regulated at the level of specific synaptic connections remains largely unknown. Here, we identify a signaling pathway that regulates the local synthesis of proteins required for the formation of excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves the regulation of the mTORC1 inhibitor Tsc2 by the receptor tyrosine kinase ErbB4, which enables the local control of mRNA translation in a cell type-specific and synapse-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins that regulates the formation of excitatory inputs on PV+ interneurons downstream of ErbB4 signaling. Our work demonstrates that local protein translation is regulated at the level of specific connections to control synapse formation in the nervous system.

neuroscience↗

bioRxiv2018

Spatiotemporally controlled genetic perturbation for efficient large-scale studies of cell non-autonomous effects

Studies in genetic model organisms have revealed much about the development and pathology of complex tissues. Most have focused on cell-intrinsic gene functions and mechanisms. Much less is known about how transformed, or otherwise functionally disrupted, cells interact with healthy ones towards a favorable or pathological outcome. This is largely due to technical limitations. We developed new genetic tools in Drosophila melanogaster that permit efficient multiplexed gain- and loss-of-function genetic perturbations with separable spatial and temporal control. Importantly, our novel tool-set is independent of the commonly used GAL4/UAS system, freeing the latter for additional, non-autonomous, genetic manipulations; and is built into a single strain, allowing one-generation interrogation of non-autonomous effects. Altogether, our design opens up efficient genome-wide screens on any deleterious phenotype. Specifically, we developed tools to study extrinsic effects on neural tumor growth but the strategy presented has endless applications within and beyond neurobiology, and in other model organisms.\n\nImpact statementA novel genetic strategy for induction of reproducible neural tumors (or any other deleterious phenotype) in a single Drosophila stock (applicable to other organisms).

developmental biology↗