Biology subjects

Oliveira Moreira, V.

Publications and source records attributed to Oliveira Moreira, V..

4 recordsLinked to original sources

bioRxiv2021

OTX2 homeoprotein functions in adult choroid plexus

Choroid plexus secretes cerebrospinal fluid important for brain development and homeostasis. The OTX2 homeoprotein is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative roles for OTX2 in choroid plexus function, including cell signaling and adhesion, and show that it regulates the expression of factors secreted into cerebrospinal fluid, notably transthyretin. We show that Otx2 expression impacts choroid plexus immune and stress responses, and also affects splicing which leads to changes in mRNA isoforms of proteins implicated in oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell autonomous target regions such as visual cortex and ventricular-subventricular zone, we identified putative targets involved in cell adhesion, chromatin structure and RNA processing. Thus, OTX2 retains important roles in choroid plexus function and brain homeostasis throughout life.

neuroscience↗

bioRxiv2020

Role of astrogial Connexin 43 in pneumococcal meningitis and pneumolysin cytotoxicity

Introductory paragraphStreptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people. The mechanism underlying PN crossing of the blood brain barrier (BBB) remains poorly understood. Here, we show that the gap junctional component connexin 43 expressed in astrocytes (aCx43) plays a major role in PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. We show a role for aCx43 in the PN-induced fragmentation of astrocytic GFAP filaments associated with bacterial translocation across endothelial vessels and replication in the brain cortex. aCx43 triggers the PN- and Ply-dependent GFAP fragmentation and nuclear shrinkage in in vitro cultured astrocytes. We showed that purified pneumolysin (Ply) co-opted Cx43 to promote the permeabilization and cytosolic calcium (Ca2+) increase of host cells, a process sensitive to extracellular ATP depletion. These results point to aCx43 as a major player during bacterial meningitis and extend cytolytic mechanisms implicating other host cell plasma membrane channels proposed for small pore-forming toxins, to Ply, a cholesterol-dependent cytolysin, at concentrations relevant to bacterial infection.

microbiology↗

bioRxiv2019

Non-cell autonomous choroid plexus-derived sAPPα regulates adult hippocampus proliferation and plasticity

Elevated amyloid precursor protein (APP) expression in the choroid plexus suggests an important role for extracellular APP metabolites in cerebrospinal fluid. Despite widespread App brain expression, we hypothesized that specifically targeting choroid plexus expression could alter animal physiology. Through various genetic and viral approaches in the adult mouse, we show that choroid plexus APP levels significantly impacted proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Given the role of A{beta} peptides in Alzheimer disease pathogenesis, we also tested whether favoring the production of A{beta} in choroid plexus could negatively affect niche functions. After AAV5-mediated long-term expression of human mutated APP specifically in the choroid plexus of adult wild type mice, we observe reduced niche proliferation, behavioral defects in reversal learning, and deficits in hippocampal long-term potentiation. Our findings highlight the unique role played by the choroid plexus in regulating brain function, and suggest that targeting APP in choroid plexus may provide a means to improve hippocampus function and alleviate disease-related burdens.

neuroscience↗

bioRxiv2018

Otx2 signals from the choroid plexus to regulate adult neurogenesis

Proliferation and migration during adult neurogenesis are regulated by a microenvironment of signaling molecules originating from local vasculature, from cerebrospinal fluid produced by the choroid plexus, and from local supporting cells including astrocytes. Here, we focus on the function of OTX2 homeoprotein transcription factor in the mouse adult ventricular-subventricular zone (V-SVZ) which generates olfactory bulb neurons. We find that OTX2 secreted by choroid plexus is transferred to supporting cells of the V-SVZ and rostral migratory stream. Deletion of Otx2 in choroid plexus affects neuroblast migration and reduces the number of olfactory bulb newborn neurons. Adult neurogenesis was also decreased by expressing secreted single-chain antibodies to sequester OTX2 in the cerebrospinal fluid, demonstrating the importance of non-cell autonomous OTX2. We show that OTX2 activity modifies extracellular matrix components and signaling molecules produced by supporting astrocytes. Thus, we reveal a multi-level and non-cell autonomous role of a homeoprotein and reinforce the choroid plexus and astrocytes as key niche compartments affecting adult neurogenesis.\n\nSignificance StatementCerebrospinal fluid, local vasculature and non-neurogenic astrocytes are niche compartments that provide a microenvironment for regulating adult mouse neurogenesis. We show that OTX2 homeoprotein secreted by choroid plexus into the cerebrospinal fluid is transferred into non-neurogenic astrocytes of the ventricular-subventricular zone and rostral migratory stream where it regulates extracellular matrix and signaling factors. This non-cell-autonomous activity impacts the number of newborn neurons that integrate the olfactory bulb. Thus, we reveal a multi-level role for OTX2 and reinforce the choroid plexus as a key niche compartment affecting adult neurogenesis.

neuroscience↗