Publications of Laurent Nguyen
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See detailVoluntary alcohol binge-drinking in adolescent C57Bl6 mice induces delayed appearance of behavioural defects in both males and females
Van Hees, Laura ULiege; Didone, Vincent ULiege; Charlet-Briart, Manon ULiege et al

in Addiction Biology (2021)

Adolescence is a developmental period characterized by significant changes in brain architecture and behaviour. The immaturity of the adolescent brain is associated with heightened vulnerability to ... [more ▼]

Adolescence is a developmental period characterized by significant changes in brain architecture and behaviour. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure may interfere with the maturation of frontal brain regions and lead to long-lasting behavioural consequences. In this study, by using a slightly modified version of the Drinking in the Dark paradigm, adolescent C57Bl6 mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of adolescent alcohol exposure (AAE), a battery of behavioural tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behaviour but rather increased anxiety- and depressive-like behaviours, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioural flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex. Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioural impairments in adulthood. [less ▲]

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See detailRoles of Nedd4-2 in the auditory portion of mouse inner ear
Pouyo, Lionel Ronald ULiege; Thelen, Nicolas ULiege; Thiry, Marc ULiege et al

Poster (2021, February)

Given the importance of protein ubiquitination in controlling various critical biological processes during development, together with a recent report identifying deafness-associated mutations in the human ... [more ▼]

Given the importance of protein ubiquitination in controlling various critical biological processes during development, together with a recent report identifying deafness-associated mutations in the human gene encoding the E3 Ubiquitin-ligase NEDD4L (Neurally Expressed and Developmentally Downregulated 4-like), we plan to uncover its implication in cochlear development and function. We first characterized the spatio-temporal expression profile of Nedd4-2, the mouse ortholog of Nedd4L, together with the closely related Nedd4-1 gene. In situ hybridization and immunohistochemistry experiments allowed us to confirm the presence of Nedd4-1 and Nedd4-2 transcripts during the embryonic stages of cochlear development. Both mRNAs are present in the sensory epithelium and the spiral ganglion. After birth, Nedd4-1 expression persists in these tissues, while Nedd4-2 transcripts were undetectable. To elucidate the role of Nedd4-2 in the inner ear, we generated conditional knockout (cKO) of Nedd4-2 in the inner ear by mating Foxg1-cre transgenic mice with Nedd4-2 Flox/flox mice. Histological analyses, Scanning Electron Microscopy, and specific immunostainings indicate that Nedd4-2 cKO cochleae develop normally during embryonic and early postnatal stages. However, similar studies performed at postnatal day 30 (P30) and later suggest an early degeneration of the hair cells and their innervating spiral ganglion neurons. Interestingly, cochlear cell loss in Nedd4-2 cKO animals follows a basal-to-apical gradient, similar to age-related or sound-induced hearing loss. Starting as early as P18, Nedd4-2 cKO are deaf, as shown by the total absence of signal in their auditory brainstem response at 90 dB. These results suggest that the severe hearing impairment impacting Nedd4-2 cKO precedes the cochlear cell loss observed around P45. Altogether, our results suggest a significant contribution of the E3 ubiquitin ligase Nedd4-2 in the developing cochlea. We are currently combining different approaches using a combination of yeast-two-hybrid, gain- and loss-of function experiments and biochemical assays to uncover the specific substrates of Nedd4-2 in the cochlea. [less ▲]

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See detailCoordination between Transport and Local Translation in Neurons
Broix, Loïc ULiege; Turchetto, Silvia ULiege; Nguyen, Laurent ULiege

in Trends in Cell Biology (2021)

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See detailLoss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis.
Rosu, Adeline ULiege; El Hachem, Najla ULiege; Rapino, Francesca ULiege et al

in The Journal of experimental medicine (2021), 218(3),

The hematopoietic system is highly sensitive to perturbations in the translational machinery, of which an emerging level of regulation lies in the epitranscriptomic modification of transfer RNAs (tRNAs ... [more ▼]

The hematopoietic system is highly sensitive to perturbations in the translational machinery, of which an emerging level of regulation lies in the epitranscriptomic modification of transfer RNAs (tRNAs). Here, we interrogate the role of tRNA anticodon modifications in hematopoiesis by using mouse models of conditional inactivation of Elp3, the catalytic subunit of Elongator that modifies wobble uridine in specific tRNAs. Loss of Elp3 causes bone marrow failure by inducing death in committing progenitors and compromises the grafting activity of hematopoietic stem cells. Mechanistically, Elp3 deficiency activates a p53-dependent checkpoint in what resembles a misguided amino acid deprivation response that is accompanied by Atf4 overactivation and increased protein synthesis. While deletion of p53 rescues hematopoiesis, loss of Elp3 prompts the development of p53-mutated leukemia/lymphoma, and inactivation of p53 and Elongator cooperatively promotes tumorigenesis. Specific tRNA-modifying enzymes thus condition differentiation and antitumor fate decisions in hematopoietic stem cells and progenitors. [less ▲]

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See detailATP-citrate lyase promotes axonal transport across species.
Even, Aviel; Morelli, Giovanni ULiege; Turchetto, Silvia ULiege et al

in Nature Communications (2021), 12(1), 5878

Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α ... [more ▼]

Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD. [less ▲]

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See detailMechanical Forces Orchestrate Brain Development.
Javier Torrent, Míriam ULiege; Zimmer-Bensch, Geraldine; Nguyen, Laurent ULiege

in Trends in neurosciences (2020)

During brain development, progenitors generate successive waves of neurons that populate distinct cerebral regions, where they settle and differentiate within layers or nuclei. While migrating and ... [more ▼]

During brain development, progenitors generate successive waves of neurons that populate distinct cerebral regions, where they settle and differentiate within layers or nuclei. While migrating and differentiating, neurons are subjected to mechanical forces arising from the extracellular matrix, and their interaction with neighboring cells. Changes in brain biomechanical properties, during its formation or aging, are converted in neural cells by mechanotransduction into intracellular signals that control key neurobiological processes. Here, we summarize recent findings that support the contribution of mechanobiology to neurodevelopment, with focus on the cerebral cortex. Also discussed are the existing toolbox and emerging technologies made available to assess and manipulate the physical properties of neurons and their environment. [less ▲]

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See detailMultifaceted actions of Zeb2 in postnatal neurogenesis from the ventricular-subventricular zone to the olfactory bulb.
Deryckere, Astrid; Stappers, Elke; Dries, Ruben et al

in Development (Cambridge, England) (2020), 147(10),

The transcription factor Zeb2 controls fate specification and subsequent differentiation and maturation of multiple cell types in various embryonic tissues. It binds many protein partners, including ... [more ▼]

The transcription factor Zeb2 controls fate specification and subsequent differentiation and maturation of multiple cell types in various embryonic tissues. It binds many protein partners, including activated Smad proteins and the NuRD co-repressor complex. How Zeb2 subdomains support cell differentiation in various contexts has remained elusive. Here, we studied the role of Zeb2 and its domains in neurogenesis and neural differentiation in the young postnatal ventricular-subventricular zone (V-SVZ), in which neural stem cells generate olfactory bulb-destined interneurons. Conditional Zeb2 knockouts and separate acute loss- and gain-of-function approaches indicated that Zeb2 is essential for controlling apoptosis and neuronal differentiation of V-SVZ progenitors before and after birth, and we identified Sox6 as a potential downstream target gene of Zeb2. Zeb2 genetic inactivation impaired the differentiation potential of the V-SVZ niche in a cell-autonomous fashion. We also provide evidence that its normal function in the V-SVZ also involves non-autonomous mechanisms. Additionally, we demonstrate distinct roles for Zeb2 protein-binding domains, suggesting that Zeb2 partners co-determine neuronal output from the mouse V-SVZ in both quantitative and qualitative ways in early postnatal life. [less ▲]

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See detailUnveiling the neurogenesis defects induced by prenatal alcohol exposure
Van Hees, Laura ULiege; Laguesse, Sophie ULiege; Nguyen, Laurent ULiege

Poster (2019, September 21)

Prenatal alcohol exposure (PAE) is known to damage the fetal brain and leads to life-long cognitive and behavioral dysfunctions. Fetal Alcohol Spectrum Disorders (FASD), which collectively describes the ... [more ▼]

Prenatal alcohol exposure (PAE) is known to damage the fetal brain and leads to life-long cognitive and behavioral dysfunctions. Fetal Alcohol Spectrum Disorders (FASD), which collectively describes the constellation of effects resulting from alcohol consumption during pregnancy, is a complex syndrome that affects up to 5% of children and is the leading cause of preventable intellectual disability. Despite prevention campaigns discouraging alcohol drinking during pregnancy, the number of children suffering from FASD has not decreased over the past years. The consequences of PAE have become a global public health problem and understanding the alcohol-related mechanisms is crucially needed to develop new pharmacological strategies and treatments. Studies have shown that alcohol interferes with the cerebral cortex development in a variety of ways, including defects in neurogenesis, impaired cell proliferation and cell migration, reduced survival and disrupted neurotransmission. However, the precise pathophysiological mechanisms underlying alco-hol’s actions on cortical development are yet poorly understood. In this study, we set up a mouse model of FASD, using an alcohol consumption paradigm in which mice voluntarily drink high amounts of alcohol throughout pregnancy. Importantly, this model avoids any bias resulting from maternal stress that could be introduced by stressful alcohol consump-tion procedures such as gavage or injection. We first showed that this model accurately reflects alcohol consumption in human, as mice reach blood alcohol concentration levels comparable to those reported in binge-drinking humans. In order to investigate alcohol-dependent corticogenesis defects, we are analyzing the number, proliferation and specifi-cation of glutamatergic projection neurons during embryonic development and at postnatal stages. By using in utero electroporation, we are investigating the migration pattern of pro-jection neurons during neurogenesis. Our preliminary results reveal an abnormal accumu-lation of neurons in deep layers of the cortex of alcohol-exposed embryos, suggesting im-paired neuronal migration or dysregulated layer specification. Analysis of radial migration at postnatal stage showed that projection neurons have finally reached the upper layer, similar to control. However, the morphology of neurons seems to be affected by prenatal alcohol exposure, especially at the level of apical dendrites. We thus plan to investigate more specifically the terminal differentiation and dendritogenesis of projection neurons of alcohol-exposed pups. We will also evaluate adult mice behavior and alcohol consumption in order to determine whether PAE has a long-term impact on adult behavior and drinking pattern. [less ▲]

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See detailUnveiling the alcohol-dependent alterations of local translation in the prefrontal cortex during adolescence
Van Hees, Laura ULiege; Nguyen, Laurent ULiege; Laguesse, Sophie ULiege

Poster (2019, September)

Alcohol use disorder (AUD) is a devastating relapsing disease which represents the fourth leading cause of preventable death worldwide. The neural mechanisms of AUD have remained uncertain, and multiple ... [more ▼]

Alcohol use disorder (AUD) is a devastating relapsing disease which represents the fourth leading cause of preventable death worldwide. The neural mechanisms of AUD have remained uncertain, and multiple genetic, psychological and environmental factors are thought to be involved. AUD has mainly been considered as a pathological condition in adults, but recent evidence suggests that the roots of alcohol addiction begin to grow during adolescence. Adolescence is a critical developmental period characterized by significant changes in brain architecture and behaviors. Brain maturation begins in posterior regions and progresses towards anterior higher-order regions, including the prefrontal cortex (PFC). The PFC is implicated in executive functions and its immaturity in adolescents is associated with lack of inhibitory control over behavior, increased impulsivity and desire of risk-taking. It is widely believed that the enhanced ability of the adolescent PFC to undergo experience-dependent changes is associated with heightened vulnerability to exogenous agents, including alcohol. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), alcohol is the most consumed drug among adolescents, with 40% reporting regularly experiencing binge-drinking episodes. This pattern of alcohol consumption is particularly harmful as it may interfere with the ongoing maturation of frontal brain circuits, leading to profound long-lasting consequences on PFC structure and function. In particular, the adolescent PFC shows structural and molecular alterations with alcohol exposure such as reduced thickness and activity, neuroimmune genes induction, loss of cholinergic neurons, aberrant dendritic spine density, and alteration of dopamine neurotransmission. In addition, adolescent alcohol exposure (AAE) is related to serious psychological problems, comorbid psychopathology and detrimental neurocognitive consequences, and clinical studies have shown that AAE significantly increases the risk of developing psychiatric and behavioral disorders later in life, including addiction. Accordingly, animal studies have reported that AAE leads to impaired PFC function associated with defective behaviors. However, the precise cellular mechanisms underlying the alcohol-induced cognitive and behavioral impairments, the molecular mechanisms underlying defects in PFC maturation, and possible sex differences are still poorly understood. Alcohol addiction is considered as a maladaptive form of learning and memory. Indeed, alcohol is thought to “usurp” the molecular mechanisms underlying those processes, including synaptic plasticity, which depends on the local translation of mRNAs at synaptic sites. It has recently been shown in adult mice that excessive alcohol consumption modifies synaptic protein composition in brain regions associated with the mesocorticolimbic pathway, promoting the development and maintenance of addiction. The mammalian target of rapamycin complex 1 (mTORC1) and the eukaryotic initiation factor 2α (eIF2α) are master regulators of local translation. We previously reported that alcohol binge-drinking in adult mice activates mTORC1 signaling in key striatal and cortical areas, enhancing synaptic protein translation and inducing neuroadaptations that in turn promote alcohol seeking and taking. Moreover, mTORC1 in the PFC is required for the retrieval of alcohol-associated memories, and has been associated with PFC development, connectivity and related behaviors. In parallel, eIF2α has been shown to regulate synaptic plasticity underlying memory and addiction, and has also been implicated in PFC function. However, the alcohol-dependent modulation of mTORC1 and eIF2α activity in the maturating PFC and the alcohol-induced defects in local translation have remained unknown. The specific aims of this project are (1) to determine whether AAE perturbs the maturation of the PFC and induces structural, physiological and/or behavioral defects; (2) to reveal whether alcohol modulates local dendritic translation via mTORC1 and/or eIF2α and leads to defective synaptic plasticity in the adolescent PFC; (3) to study the AAE-induced local translation alterations in specific neuronal subtypes and identify mRNA candidates. This work aims to provide new insight on the molecular mechanisms underlying alcohol’s actions in the maturating PFC by focusing on local translation. By using a mouse model of voluntary adolescent binge drinking, we showed that excessive alcohol consumption during adolescence leads to long-lasting behavioral impairments in adulthood, such as increased anxiety and alcohol intake, as well as reduced cognitive performances. We also report that AAE increases mTORC1 signaling in the PFC of adolescent mice. By using transgenic mouse lines and Ribotag profiling, we are comparing the synaptic translatome of specific neuronal populations in the PFC (i.e. glutamatergic neurons and interneurons) in order to identify candidate synaptic mRNAs whose translation levels are modified by AAE. [less ▲]

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See detailL’expérimentation animale : toujours une nécessité pour la santé animale et humaine
Balthazart, Jacques ULiege; Blanpain, Cédric; Bureau, Fabrice ULiege et al

Article for general public (2019)

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l ... [more ▼]

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l'une des premières causes de décès en Belgique. Cet article soulignait l'importance de la recherche fondamentales et du passage nécessaire par l'expérimentation préclinique (animale) pour développer une application chez l’humain. En réaction, Solange T'Kint, administratrice de l'ASBL S.E.A. - Suppression des Expériences sur l'Animal-, publiait le 2 juillet dans « La Libre » un nouveau pamphlet contre l'expérimentation animale. Mme T Kint avait déjà lancé en aout 2018 une pétition attaquant la découverte3 d'un chercheur de l'ULB sur la dépendance aux drogues réalisée chez la souris , démontrant par là à quel point toute avancée médicale imputable à l'expérimentation animale lui est insupportable. Ici se trouve la réponse de Scientifiques qui pensent indispensable d’informer chacun-e- de manière rigoureuse et de ne jamais laisser diffuser de « fake news » sans réagir. [less ▲]

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See detailUnveiling the neurogenesis defects induced by prenatal alcohol exposure
Van Hees, Laura ULiege; Laguesse, Sophie ULiege; Nguyen, Laurent ULiege

Poster (2019, June 13)

Prenatal alcohol exposure (PAE) is known to damage the fetal brain and lead to life-long cognitive and behavioral dysfunctions. Alcohol is believed to interfere with the cerebral cortex development in a ... [more ▼]

Prenatal alcohol exposure (PAE) is known to damage the fetal brain and lead to life-long cognitive and behavioral dysfunctions. Alcohol is believed to interfere with the cerebral cortex development in a variety of ways; however, the precise pathophysiological mechanisms underlying alcohol’s actions are yet poorly understood. In this study, we use pregnant mice voluntarily drinking high amounts of alcohol throughout pregnancy as a model of Fetal Alcohol Spectrum Disorder, and showed that mice reach blood alcohol concentration levels comparable to those reported in binge-drinking humans. We investigated the alcohol-dependent corticogenesis defects, by analyzing the survival, proliferation, specification and migration of projection neurons during embryonic development. By using in utero electroporation, we observed delayed neuronal migration in the sensory cortex of alcohol-exposed embryos. We are now studying the different steps of radial migration by using time-lapse imaging in organotypic slices, to precisely define the alcohol-induced defects on radial migration of projection neurons. Moreover, in order to determine whether PAE has a long-term impact on behavior, we investigated tactile sensitivity by using the adhesive removal test. Our preliminary results have shown that alcohol-exposed females exhibit both increased initial contact time (sensory component) and removal time (motor component), compared to control females, but no difference was observed in males, suggesting sex-specific long-lasting impairment of sensory motor cortical regions induced by PAE. We plan to perform additional behavioral tests to evaluate anxiety levels (open-field, elevated-plus maze), and sociability (three chamber test). [less ▲]

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See detailCell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis.
Gomes Da Silva, Carla ULiege; Peyre, Elise; Nguyen, Laurent ULiege

in Nature Reviews. Neuroscience (2019)

The cerebral cortex is an evolutionarily advanced brain structure that computes higher motor, sensory and cognitive functions. Its complex organization reflects the exquisite cell migration and ... [more ▼]

The cerebral cortex is an evolutionarily advanced brain structure that computes higher motor, sensory and cognitive functions. Its complex organization reflects the exquisite cell migration and differentiation patterns that take place during embryogenesis. Recent evidence supports an essential role for cell migration in shaping the developing cerebral cortex via direct cellular contacts and spatially organized diffusible cues that regulate the establishment of its cytoarchitecture and function. Identifying the nature of the crosstalk between cell populations at play during brain development is key to understanding how cerebral cortical morphogenesis proceeds in health and disease. [less ▲]

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See detailProteostasis is essential during cochlear development for neuron survival and hair cell polarity
Freeman, Stephen ULiege; Mateo Sánchez, Susana ULiege; Pouyo, Ronald ULiege et al

in EMBO Reports (2019), 20(9),

Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age-related diseases, including hearing loss ... [more ▼]

Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age-related diseases, including hearing loss. Here, we show that altered proteostasis consequent to Elongator complex deficiency also impacts the proper development of the cochlea and results in deafness. In the absence of the catalytic subunit Elp3, differentiating spiral ganglion neurons display large aggresome-like structures and undergo apoptosis before birth. The cochlear mechanosensory cells are able to survive proteostasis disruption but suffer defects in polarity and stereociliary bundle morphogenesis. We demonstrate that protein aggregates accumulate at the apical surface of hair cells, where they cause a local slowdown of microtubular trafficking, altering the distribution of intrinsic polarity proteins and affecting kinocilium position and length. Alleviation of protein misfolding using the chemical chaperone 4-phenylbutyric acid during embryonic development ameliorates hair cell polarity in Elp3-deficient animals. Our study highlights the importance of developmental proteostasis in the cochlea and unveils an unexpected link between proteome integrity and polarized organization of cellular components. © 2019 The Authors [less ▲]

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See detailTemporal patterning of apical progenitors and their daughter neurons in the developing neocortex.
Telley, L.; Agirman, Gulistan ULiege; Prados, J. et al

in Science (2019), 364(6440),

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell ... [more ▼]

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age-dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity. [less ▲]

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See detailZika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway.
Ferraris, Pauline; Cochet, Marielle; Hamel, Rodolphe et al

in Emerging microbes & infections (2019), 8(1), 1003-1016

Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been ... [more ▼]

Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been shown to directly infect human neural progenitor cells (hNPCs), thereby decreasing their viability and growth, it is as yet unknown which of the cellular pathways involved in the disruption of neurogenesis are affected following ZIKV infection. By comparing the effect of two ZIKV strains in vitro on hNPCs, the differentiation process of the latter cells was found to lead to a decreased susceptibility to infection and cell death induced by each of the ZIKV strains, which was associated with an earlier and stronger antiviral innate immune response in infected, differentiated hNPCs, as compared to undifferentiated cells. Moreover, ZIKV modulated, both in hNPCs and in vivo in fetal brain in an experimental mouse model, the expression of the Notch pathway which is involved in cellular proliferation, apoptosis and differentiation during neurogenesis. These results show that the differentiation state of hNPCs is a significant factor contributing to the outcome of ZIKV infection and furthermore suggest that ZIKV infection might initiate early activation of the Notch pathway resulting in an abnormal differentiation process, implicated in ZIKV-induced brain injury. [less ▲]

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See detailBuilding Bridges Between the Clinic and the Laboratory: A Meeting Review - Brain Malformations: A Roadmap for Future Research.
Sapir, Tamar; Barakat, Tahsin Stefan; Paredes, Mercedes F. et al

in Frontiers in cellular neuroscience (2019), 13

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific ... [more ▼]

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting. [less ▲]

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See detailA clinical and histopathological study of malformations observed in fetuses infected by the Zika virus
Beaufrère, Aurélie; Bessières, Bettina; Bonnière, Maryse et al

in Brain Pathology (2019), 29(1), 114-125

Background: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo fetal development. The ... [more ▼]

Background: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo fetal development. The aim of the present study is to provide a detailed clinical and histopathological study of the fetal disruption caused by the ZIKV, with a special focus on the associated neuropathological findings. Methods: A detailed feto-placental examination, as well as neuropathological and neurobiological studies were performed on three fetuses collected after pregnancy termination between 22 and 25 weeks of gestation (WG), because brain malformations associated with a maternal and fetal ZIKV infection was diagnosed. Results: In all three cases, the maternal infection occurred during the first trimester of pregnancy. A small head was observed on the ultrasound examination of the second trimester of pregnancy and led to the diagnosis of ZIKV fetopathy and pregnancy termination. The fetal histopathological examination was unremarkable on the viscera but showed on the testis an interstitial lymphocytic infiltrate. The placenta contained a Hofbauer cells hyperplasia with signs of inflammation. Neuropathological findings included a meningoencephalitis and an ex vacuo hydrocephalus. Immunohistochemical studies showed the presence of T lymphocytic and histiocytic meningitis associated with an abundant cerebral astroglial and macrophagic reaction. In situ hybridization demonstrated, abundant ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate. In addition massive cells death and endoplasmic reticulum damage were present. Conclusion: The present study reports on the clinical and histopathological findings observed in three fetuses infected by the ZIKV. It emphasizes the severity of brain damages and the minimal visceral and placental changes observed upon ZIKV infection. This confirms the selective neurotropism of ZIKV. Finally, it allows us to describe the cascade of multifactorial developmental defects leading to microcephaly. © 2018 International Society of Neuropathology [less ▲]

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See detailATAT1-enriched vesicles promote microtubule acetylation via axonal transport.
Even, Aviel; Morelli, Giovanni ULiege; Broix, Loïc ULiege et al

in Science Advances (2019), 5(12), 2705

Microtubules are polymerized dimers of alpha- and beta-tubulin that underlie a broad range of cellular activities. Acetylation of alpha-tubulin by the acetyltransferase ATAT1 modulates microtubule ... [more ▼]

Microtubules are polymerized dimers of alpha- and beta-tubulin that underlie a broad range of cellular activities. Acetylation of alpha-tubulin by the acetyltransferase ATAT1 modulates microtubule dynamics and functions in neurons. However, it remains unclear how this enzyme acetylates microtubules over long distances in axons. Here, we show that loss of ATAT1 impairs axonal transport in neurons in vivo, and cell-free motility assays confirm a requirement of alpha-tubulin acetylation for proper bidirectional vesicular transport. Moreover, we demonstrate that the main cellular pool of ATAT1 is transported at the cytosolic side of neuronal vesicles that are moving along axons. Together, our data suggest that axonal transport of ATAT1-enriched vesicles is the predominant driver of alpha-tubulin acetylation in axons. [less ▲]

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