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Zika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH‐associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV‐induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or CEP63 loss decreased the centrosomal localization and stability of TANK‐binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection also increased the centrosomal accumulation of the CEP63 interactor DTX4, a ubiquitin ligase that degrades TBK1. Therefore, we propose that ZIKV disrupts CEP63 function to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response. Synopsis: Brazilian Zika virus (ZIKV) infection disrupts centrosome organization and destabilizes TBK1, thereby dampening innate immune response activation. ZIKV protein NS3 localizes to the centrosome and redistributes the microcephaly‐associated protein CEP63 from the centrosome.Acentrosomal CEP63 recruits the ubiquitin ligase DTX4 leading to the degradation of TBK1, a regulator of innate immunity.TBK1 loss prevents the activation of the innate immune response in ZIKV‐infected cells. [ABSTRACT FROM AUTHOR]

Neuroserpin is a serine‐protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia‐ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is still no information in the literature on its distribution during human brain development. The present study provides a detailed description of the changing spatiotemporal patterns of neuroserpin focusing on physiological human brain development. Five stages were distinguished within our examined age range which spanned from the 7th gestational week until adulthood. In particular, subplate and deep cortical plate neurons were identified as the main sources of neuroserpin production between the 25th gestational week and the first postnatal month. Our immunohistochemical findings were substantiated by single cell RNA sequencing data showing specific neuronal and glial cell types expressing neuroserpin. The characterization of neuroserpin expression during physiological human brain development is essential for forthcoming studies which will explore its involvement in pathological conditions, such as perinatal hypoxia‐ischaemia and adult stroke in human. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme ( GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth factor ( EGF) and platelet-derived growth factor ( PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in GBM. However, clinical trials of tyrosine-kinase inhibitors have shown disappointing efficacy, in part due to intra-tumor heterogeneity. To assess the effect of clonal heterogeneity on gene expression, we derived an approach to map single-cell expression profiles to sequentially acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. Descending the phylogenetic tree of a PDGF-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type, expressing pro-angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed an up-regulation of pro-invasive genes. An in-frame deletion in a specific dimerization domain of PDGF receptor correlates with an up-regulation of growth pathways in a proneural GBM and enhances proliferation when ectopically expressed in glioma cell lines. In-frame deletions in this domain are frequent in public GBM data. [ABSTRACT FROM AUTHOR]

Of the many signals in the developing nervous system, GABA (γ-aminobutyric acid) has been shown to be one of the earliest neurotransmitters present. Unlike in the adult, where this transmitter acts synaptically to inhibit neurons, during development, GABA can depolarize progenitor cells and their progeny due to their high intracellular chloride concentration. This early form of GABA signalling may provide the main excitatory drive for the immature cortical network and play a central role in regulating cortical development. Many features of GABA signalling are conserved in different species and are recapitulated during neurogenesis in the adult brain, demonstrating the importance of this versatile molecule in driving cortical formation. Here, we present recent evidence supporting the multiple functions of GABA during embryonic development and adult neurogenesis, from regulating progenitor proliferation to influencing the migration and maturation of newborn neurons. [ABSTRACT FROM AUTHOR]

Two distinct populations of cerebral cortical progenitor cells that generate neurons during embryogenesis have been identified: radial glial cells and intermediate progenitor cells. Despite advances in our understanding of progenitor cell populations, we know relatively little about factors that regulate their proliferative behaviour. 17-β-Estradiol (E2) is present in the adult and developing mammalian brain, and plays an important role in central nervous system processes such as neuronal differentiation, survival and plasticity. E2 also stimulates neurogenesis in the adult dentate gyrus. We examined the role of E2 during embryonic cortical neurogenesis through immunohistochemistry, in situ hybridization, functional enzyme assay, organotypic culture and in utero administration of estradiol-blocking agents in mice. We show that aromatase, the E2 synthesizing enzyme, is present in the embryonic neocortex, that estrogen receptor-α is present in progenitor cells during cortical neurogenesis, that in vitro E2 administration rapidly promotes proliferation, and that in utero blockade of estrogen receptors decreases proliferation of embryonic cortical progenitor cells. Furthermore, the E2 inhibitor α-fetoprotein is expressed at high levels by radial glial cells but at lower levels by intermediate progenitor cells, suggesting that E2 differentially influences the proliferation of these cortical progenitor cell types. These findings demonstrate a new functional role for E2 as a proliferative agent during critical stages of cerebral cortex development. [ABSTRACT FROM AUTHOR]

Our knowledge of the proliferation, migration, and differentiation of neurons has changed dramatically over the last 10 years. Whereas traditionally it was thought that glial and neuronal cells were separate cell lines with different lineages, we now know that this is not true. Radial glia are a type of neural stem cell that generate excitatory pyramidal neurons directly through asymmetric cell division in the ventricular zone (VZ) of the telencephalon and indirectly through the symmetric division of daughter intermediate precursor cells that divide in the subventricular zone (SVZ). Moreover, pyramidal neurons, once thought to migrate only along radial guide fibers to the developing layers of the cortex, have been shown to proceed through four distinct stages of migration during which they change shape, direction, and speed. Gamma-aminobutyric acid (GABAergic) inhibitory interneurons, on the other hand, are generated not in the cortex, but in the medial ganglionic eminence and migrate tangentially to their final cortical destinations. Evidence suggests that GABA activation may play a role in coordinating the generation and migration of both pyramidal and interneuron populations. At the end of neurogenesis, radial glial cells translocate to the cortex and transform into astrocytes. Although they do not actively divide in the adult brain, astrocytes may retain the potential to generate new neurons. These new findings have increased our understanding of the mechanisms underlying certain developmental disorders and, in doing so, reveal potentially useful modes of therapeutic intervention. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Cortical dysplasia (CD) is associated with epilepsy in both the pediatric and adult populations. The mechanism underlying seizures with cortical malformations is still poorly understood. To study the physiology of dysplastic cortex, we developed an experimental model of CD. Methods: Pregnant rats were given intraperitoneal injections of carmustine (1-3-bis-chloroethyl-nitrosourea; BCNU) on embryonic day 15 (E15). Cortical histology was examined in the resulting pups at P0, P28, and P60. In addition, evoked and spontaneous field potential recordings were obtained in cortical slices from adult control and BCNU-exposed rats. Finally, we used whole-cell recordings to compare physiologic properties of pyramidal neurons and γ-aminobutyric acid (GABA) responses in control and BCNU-treated animals. Results: Features characteristic of CD were found in the offspring, including laminar disorganization, cytomegalic neurons, and neuronal heterotopias. Dysplastic cortex also contained abnormal clusters of Cajal–Retzius (CR) cells and disruption of radial glial fibers, as demonstrated with immunohistochemistry. Under conditions of partial GABAA -receptor blockade with 10 μM bicuculline methiodide (BMI), slices of dysplastic cortex demonstrated a significant increase in the number of spontaneous and evoked epileptiform discharges. Individual pyramidal neurons in dysplastic cortex were less sensitive to application of GABA compared with controls. Conclusions: BCNU exposure in utero produces histologic alterations suggestive of CD in rat offspring. Dysplastic cortex from this model demonstrates features of hyperexcitability and decreased neuronal sensitivity to GABA. Such physiologic alterations may underlie the increased epileptogenicity of dysplastic cortex. [ABSTRACT FROM AUTHOR]