Biology subjects

Foa, L.

Publications and source records attributed to Foa, L..

3 recordsLinked to original sources

bioRxiv2026

Disruption of the Homer1 coiled-coiled domain by a novel de novo human HOMER1 variant impairs protein scaffolding, calcium signalling, and synaptogenesis

Rare de novo variants in synaptic scaffolding proteins are increasingly recognized for their roles in driving abnormal neuronal connectivity underlying conditions such as epilepsy and autism spectrum disorder (ASD). Homer1b/c, a synaptic scaffolding protein, regulates a wide suite of synaptic functions including Ca2+ signalling, dendritic spine morphogenesis and multiple forms of synaptic plasticity. Here we report a novel substitution mutation in the human HOMER1 gene, HOMER1R297W, and demonstrate that Homer1b/cR297W expression dominant-negative like effect on Homer1-dependent functions. In dorsal root ganglion (DRG) sensory neurons, Homer1b/c1R297W impairs axonal growth cone turning to gradients of brain-derived neurotrophic factor (BDNF), a process that requires functional store-operated Ca2+ entry (SOCE). Accordingly, we found that SOCE was significantly blunted in both Homer1b/cR297W DRG growth cones and hippocampal neuron soma. In hippocampal neurons, Homer1b/cR297W lowered dendritic spine density and reduced endoplasmic reticulum infiltration into spines. Homer1b/cR297W hippocampal neurons also exhibited decreased synaptic metabotropic glutamate receptor 5 (mGluR5) expression and blunted dendritic Ca{superscript 2} increases following group-I mGluR activation. Super resolution imaging using direct stochastic optical reconstruction microscopy (dSTORM) further demonstrated that Homer1b/cR297W diminishes receptor clustering, uncoupling it from crucial binding partners including IP3R, mGluR5 and STIM1/2. Taken together, these findings highlight the importance of Homer1b/cs tetrameric scaffolding in shaping axon guidance, dendritic spine dynamics and synaptic Ca{superscript 2} signalling. Disruption of these processes by Homer1b/cR297W offers valuable mechanistic insights into how rare de novo variants and altered protein scaffolding can contribute to the connectivity deficits implicated in neurodevelopmental and neurological disorders.

neuroscience↗

bioRxiv2023

Optogenetic inhibition of Gα signalling alters and regulates circuit functionality and early circuit formation

Optogenetic techniques provide genetically targeted, spatially and temporally precise approaches to correlate cellular activities and physiological outcomes. In the nervous system, G-protein-coupled receptors (GPCRs) have essential neuromodulatory functions through binding extracellular ligands to induce intracellular signaling cascades. In this work, we develop and validate a new optogenetic tool that disrupt Gq signaling through membrane recruitment of a minimal Regulator of G-protein signaling (RGS) domain. This approach, Photo-induced Modulation of G protein - Inhibition of Gq (PiGM-Iq), exhibited potent and selective inhibition of Gq signaling. We alter the behavior of C. elegans and Drosophila with outcomes consistent with GPCR-Gq disruption. PiGM-Iq also changes axon guidance in culture dorsal root ganglia neurons in response to serotonin. PiGM-Iq activation leads to developmental deficits in zebrafish embryos and larvae resulting in altered neuronal wiring and behavior. By altering the choice of minimal RGS domain, we also show that this approach is amenable to Gi signaling.

neuroscience↗

bioRxiv2020

Low-density lipoprotein receptor-related protein 1 (LRP1) is a negative regulator of oligodendrocyte progenitor cell differentiation in the adult mouse brain.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a large, endocytic cell surface receptor that is highly expressed by oligodendrocyte progenitor cells (OPCs), and LRP1 expression is rapidly downregulated as OPCs differentiate into oligodendrocytes (OLs). We report that the conditional deletion of Lrp1 from adult mouse OPCs (Pdgfr-CreER :: Lrp1fl/fl) increases the number of new myelinating OLs added to brain, but that each new cell elaborates a normal quantity of myelin. OPC proliferation is also elevated following Lrp1 deletion in vivo, however, this is likely to be a secondary, homeostatic response to increased OPC differentiation, as our in vitro experiments show that LRP1 is a direct negative regulator of OPC differentiation, not proliferation. Deleting Lrp1 from adult OPCs also enhances remyelination, as cuprizone-induced lesions are smaller in Lrp1-deleted mice, and parenchymal OPCs produce a larger number of mature OLs. These data suggest that the selective blockade of LRP1 function on adult OPCs may enhance myelin repair in demyelinating diseases, such as multiple sclerosis.

neuroscience↗