References of "Malgrange, Brigitte"
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See detailUsing human pluripotent stem cells to untangle neurodegenerative disease mechanisms
Malgrange, Brigitte ULg; Borgs, Laurence ULg; Grobarczyk, Benjamin ULg et al

in Cellular and Molecular Life Sciences : CMLS (2011), 68(4), 635-49

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all ... [more ▼]

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all cell types of the nervous system. While human pluripotent cell-based therapies are unlikely to arise soon, these cells can currently be used as an inexhaustible source of committed neurons to perform high-throughput screening and safety testing of new candidate drugs. Here, we describe critically the available methods and molecular factors that are used to direct the differentiation of hES or hiPS into specific neurons. In addition, we discuss how the availability of patient-specific hiPS offers a unique opportunity to model inheritable neurodegenerative diseases and untangle their pathological mechanisms, or to validate drugs that would prevent the onset or the progression of these neurological disorders. [less ▲]

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See detailStructure and development of cochlear afferent innervation in mammals.
Defourny, Jean ULg; Lallemend, Francois; Malgrange, Brigitte ULg

in American Journal of Physiology - Cell Physiology (2011), 301(4), 750-61

In mammals, sensorineural deafness results from damage to the auditory receptors of the inner ear, the nerve pathways to the brain or the cortical area that receives sound information. In this review, we ... [more ▼]

In mammals, sensorineural deafness results from damage to the auditory receptors of the inner ear, the nerve pathways to the brain or the cortical area that receives sound information. In this review, we first focused on the cellular and molecular events taking part to spiral ganglion axon growth, extension to the organ of Corti, and refinement. In the second half, we considered the functional maturation of synaptic contacts between sensory hair cells and their afferent projections. A better understanding of all these processes could open insights into novel therapeutic strategies aimed to re-establish primary connections from sound transducers to the ascending auditory nerve pathways. [less ▲]

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See detailHearing Preservation in Cochlear Implantation and Drug Treatment.
Barriat, Sébastien ULg; Poirrier, Anne-Lise ULg; Malgrange, Brigitte ULg et al

in Advances in Oto-Rhino-Laryngology (2010), 67

Insertion of an electrode array into the cochlea produces immediate damage to the inner ear, which is responsible for a hearing loss. In addition, a delayed hearing loss can be observed. In order to ... [more ▼]

Insertion of an electrode array into the cochlea produces immediate damage to the inner ear, which is responsible for a hearing loss. In addition, a delayed hearing loss can be observed. In order to maximize hearing preservation after insertion of an electrode and to enhance the performance of the cochlear implant, it has been proposed to deliver pharmacological agents to the inner ear. Molecules can be administered locally to the inner ear through a direct perilymphatic perfusion or through the round window membrane. These modalities of treatment have already been successfully applied to some patients with inner ear diseases. In this paper, we will review some basic aspects of drug delivery to the inner ear to prevent the degeneration of the neurosensory hair cells and auditory neurons, and the actual applicability to humans in order to maintain hearing function after the insertion of electrodes of a cochlear implant. [less ▲]

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See detailOtotoxic drugs: difference in sensitivity between mice and guinea pigs.
Poirrier, Anne-Lise ULg; Van Den Ackerveken, Priscilla ULg; Kim, T. S. et al

in Toxicology Letters (2010), 193(1), 41-9

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to ... [more ▼]

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to develop an adult mouse model of ototoxic drug-induced hearing loss and to compare the ototoxicity in the adult mouse to that in the well-described guinea pig model. Mice are a powerful model organism, especially due to the large availability of antibodies, probes and genetic mutants. In this study, mice (n=114) and guinea pigs (n=35) underwent systemic treatment with either kanamycin or cisplatin. Auditory brainstem responses showed a significant threshold shift in guinea pigs 2 weeks after the beginning of the ototoxic treatment, while there was no significant hearing impairment recorded in mice. Hair cells and neuronal loss were correlated with hearing function in both guinea pigs and mice. These results indicate that the mouse is not a good model for ototoxicity, which should be taken into consideration in all further investigations concerning ototoxicity-induced hearing loss. [less ▲]

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See detailOxidative Stress in the Cochlea: An Update.
Poirrier, Anne-Lise ULg; Pincemail, Joël ULg; Van Den Ackerveken, Priscilla ULg et al

in Current Medicinal Chemistry (2010)

This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the molecular and biochemical pathways responsible for the regulation of ... [more ▼]

This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the molecular and biochemical pathways responsible for the regulation of the survival of hair cells and spiral ganglion neurons in the auditory portion of the inner ear. The pivotal role of ROS/RNS in ototoxicity makes them potentially valuable candidates for effective otoprotective strategies. In this review, we describe the major characteristics of ROS/RNS and the different oxidative processes observed during ototoxic cascades. At each step, we discuss their potential as therapeutic targets because an increasing number of compounds that modulate ROS/RNS processing or targets are being identified. [less ▲]

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See detailGlial but not neuronal development in the cochleo-vestibular ganglion requires Sox10.
Breuskin, Ingrid ULg; Bodson, Morgan ULg; Thelen, Nicolas ULg et al

in Journal of Neurochemistry (2010), 114(6), 1827-39

The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known about the molecular mechanisms that ... [more ▼]

The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known about the molecular mechanisms that regulate the tightly orchestrated development of this structure. Here, we report that Sox10, a high-mobility group DNA-binding domain transcription factor that is required for the proper development of neural crest cell derivatives, is specifically expressed in post-migratory neural crest cells in the cochleo-vestibular ganglion. Using Sox10-deficient mice, we demonstrate that this transcription factor is essential for the survival, but not the generation, of the post-migratory neural crest cells within the inner ear. In the absence of these neural crest-derived cells, we have investigated the survival of the otocyst-derived auditory neurons. Surprisingly, auditory neuron differentiation, sensory target innervation and survival are conserved despite the absence of glial cells. Moreover, brain-derived neurotrophic factor expression is increased in the hair cells of Sox10-deficient mice, a compensatory mechanism that may prevent spiral ganglion neuronal cell death. Taken together, these data suggest that in the absence of neural crest-derived glial cells, an increase trophic support from hair cells promotes the survival of spiral ganglion neurons in Sox10 mutant mice. [less ▲]

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See detailSPATIO-TEMPORAL LOCALIZATION OF INTERMEDIATE FILAMENTS IN THE ORGAN OF CORTI BETWEEN THE EMBRYONIC DAY 18 (E18) AND THE POST-NATAL DAY 15 (P15) IN RAT
Johnen, Nicolas ULg; Thelen, Nicolas ULg; Malgrange, Brigitte ULg et al

Poster (2009, October 17)

The mammalian auditory organ, the organ of Corti (OC), is composed of mechanosensory hair cells and nonsensory supporting cell types. Based on their morphology and physiology, a least four types of ... [more ▼]

The mammalian auditory organ, the organ of Corti (OC), is composed of mechanosensory hair cells and nonsensory supporting cell types. Based on their morphology and physiology, a least four types of supporting cells can be identified in the OC: inner pillar cell, outer pillar cell, phalangeal cell and Deiter’s cells. The structure of this organ is well reported in adult but its development is still little known. Using antibodies directed against different proteins of intermediate filaments cytoskeleton, we studied the spatial-temporal localization of cytokeratins (typical of epithelial cells) and vimentin (typical of mesenchymal cells) during the differentiation of the OC in rat from the embryonic day 18 (E18) to the postnatal day (P15). Whatever the antibody used, we observed an obvious labelling over the supporting cells after the birth. In particular, an intense labelling is observed in the pillar cells and in the Deiters’ cells at P8 and at P10. These results suggest that the epithelial-mesenchymal transition might be implicated in the opening of Corti’s tunnel between the pillar cells and the formation of the Nuel’s spaces between the Deiters’ cell and their outer hair cells, at P8 and at P10 respectively. [less ▲]

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See detailHair cell progenitors: identification and regulatory genes
Bodson, Morgan ULg; Breuskin, Ingrid ULg; Lefèbvre, Philippe ULg et al

in Acta Oto-Laryngologica (2009), 10

Hair cell loss in higher vertebrates appears to be permanent. Progenitors that are quiescent in the organ of Corti are the best candidates for the restoration of the different cell types in the organ of ... [more ▼]

Hair cell loss in higher vertebrates appears to be permanent. Progenitors that are quiescent in the organ of Corti are the best candidates for the restoration of the different cell types in the organ of Corti. However, little is known about the presence of these progenitors and their capacity to differentiate into hair cells. This review will first highlight recent findings concerning the identification of progenitor cells that are able to proliferate and to differentiate into hair cells. Principal factors impinging on this process are then reviewed. Auditory hair cell progenitors have been identified and, under appropriate conditions, are capable of proliferating and differentiating into hair cells. Characterization of signals that maintain, expand and regulate these progenitors will be essential for the biomedical application of stem cell populations to restore hearing. [less ▲]

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See detailExpression patterns of miR-96, miR-182 and miR-183 in the development inner ear
Sacheli, Rosalie ULg; Nguyen, Laurent ULg; Borgs, Laurence ULg et al

in Gene Expression Patterns (2009)

MicroRNAs (miRNAs) constitute a class of small non-coding endogenous RNAs that downregulate gene expression by binding to 3' untranslated region (UTR) of target messenger RNAs. Although they have been ... [more ▼]

MicroRNAs (miRNAs) constitute a class of small non-coding endogenous RNAs that downregulate gene expression by binding to 3' untranslated region (UTR) of target messenger RNAs. Although they have been found to regulate developmental and physiological processes in several organs and tissues, their role in the regulation of the inner ear transcriptome remains unknown. In this report, we have performed systematic in situ hybridization to analyze the temporal and spatial distribution of three miRNAs (miR-96, mR-182, and mR-183) that are likely to arise from a single precursor RNA during the development and the maturation of the cochlea. Strikingly we found that the expression of mR-96, mR-182 and mR-183 was highly dynamic during the development of the cochlea, from the patterning to the differentiation of the main cochlear structures. [less ▲]

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See detailSupporting cell cytoskeleton during development of the organ of Corti in rat
Johnen, Nicolas ULg; Thelen, Nicolas ULg; Malgrange, Brigitte ULg et al

Poster (2009, May 11)

The mammalian auditory organ, the organ of Corti (OC), is composed of mechanosensory hair cells and nonsensory supporting cell types. Based on their morphology and physiology, a least four types of ... [more ▼]

The mammalian auditory organ, the organ of Corti (OC), is composed of mechanosensory hair cells and nonsensory supporting cell types. Based on their morphology and physiology, a least four types of supporting cells can be identified in the OC: inner pillar cell, outer pillar cell, phalangeal cell and Deiter’s cells. All supporting cells are highly specialized cells that are characterized by the presence of bundled microtubules with 15 protofilaments instead of 13. Using antibobies against different proteins of cytoskeleton (tubulin, cutokeratin and vimentin), we investigated by confocal microscopy the setting up of supporting cells' cytoskeleton during the differentiation of the OC in art from the embryonic day 18 (E18) to the postnatal 15 (P15). We showed that the inner pillar cells are labelled with an anti-beta IV tubulin from P0. Using an antibody to cytokeratin, a labelling appeared in Deiters' cells from E22. We also revealed that during the development of the OC, supporting cells were labelled with an anti-vimentin antibody from P0. [less ▲]

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See detailElongator controls the migration and differentiation of cortical neurons through acetylation of a tubulin
Creppe, Catherine ULg; Malinouskaya, Lina ULg; Volvert, Marie-Laure ULg et al

in Cell (2009), 136

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which ... [more ▼]

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha tubulin. A direct reduction of alpha tubulin acetylation leads to comparable defects in cortical neurons and suggests that alpha tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons. [less ▲]

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See detailRole of ephrin-A5 in the survival and connectivity of spiral ganglion neurons.
Defourny, Jean ULg; POIRRIER, Anne-Lise ULg; Hadjab, Saida et al

Poster (2009)

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See detailAdult neurogenesis and the diseased brain.
Vandenbosch, Renaud ULg; Borgs, Laurence ULg; Beukelaers, Pierre ULg et al

in Current Medicinal Chemistry (2009), 16(6), 652-66

For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification ... [more ▼]

For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification of adult neural stem cells (NSCs) and evidence regarding a continuous production of neurons throughout life in the dentate gyrus (DG) and the subventricular zone of the lateral ventricles (SVZ), have provided new hopes for the development of novel therapeutic strategies to induce regeneration in the damaged brain. Moreover, proofs have accumulated this last decade that endogenous stem/progenitor cells of the adult brain have an intrinsic capacity to respond to brain disorders. Here, we first briefly summarize our current knowledge related to adult neurogenesis before focusing on the behaviour of adult neural stem/progenitors cells following stroke and seizure, and describe some of the molecular cues involved in the response of these cells to injury. In the second part, we outline the consequences of three main neurodegenerative disorders on adult neurogenesis and we discuss the potential therapeutic implication of adult neural stem/progenitors cells during the course of these diseases. [less ▲]

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See detailCell "circadian" cycle: new role for mammalian core clock genes.
Borgs, Laurence ULg; Beukelaers, Pierre ULg; Vandenbosch, Renaud ULg et al

in Cell Cycle (Georgetown, Tex.) (2009), 8(6), 832-7

In mammals, 24 hours rhythms are organized as a biochemical network of molecular clocks that are operative in all tissues, with the master clock residing in the hypothalamic suprachiasmatic nucleus (SCN ... [more ▼]

In mammals, 24 hours rhythms are organized as a biochemical network of molecular clocks that are operative in all tissues, with the master clock residing in the hypothalamic suprachiasmatic nucleus (SCN). The core pacemakers of these clocks consist of auto-regulatory transcriptional/post-transcriptional feedback loops. Several lines of evidence suggest the existence of a crosstalk between molecules that are responsible for the generation of circadian rhythms and molecules that control the cell cycle progression. In addition, highly specialized cell cycle checkpoints involved in DNA repair after damage seem also, at least in part, mediated by clock proteins. Recent studies have also highlighted a putative connection between clock protein dysfunction and cancer progression. This review discusses the intimate relation that exists between cell cycle progression and components of the circadian machinery. [less ▲]

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See detailPeriod 2 regulates neural stem/progenitor cell proliferation in the adult hippocampus.
Borgs, Laurence ULg; Beukelaers, Pierre ULg; Vandenbosch, Renaud ULg et al

in BMC Neuroscience (2009), 10

BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light ... [more ▼]

BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG. RESULTS: In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death. CONCLUSION: Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice. [less ▲]

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See detailSox10 promotes the survival of cochlear progenitors during the establishment of the organ of Corti
Breuskin, Ingrid ULg; Bodson, Morgan ULg; Thelen, Nicolas ULg et al

in Developmental Biology (2009), 15(335), 327-339

Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that ... [more ▼]

Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that Sox10 is initially expressed throughout the otic vesicle epithelium and becomes later restricted to supporting cells as cell differentiation proceeds in the organ of Corti. Morphological analyses of Sox10 mutant mice reveal a significant shortening of the cochlear duct likely resulting from the progressive depletion of cochlear progenitors. While Sox10 appears dispensable for the differentiation and patterning of the inner ear prosensory progenitors, our data support a critical role for this transcription factor in the promotion of their survival. We provide genetic evidences that Sox10, in a concentration-dependant manner, could play a role in the regulation of Jagged1, a gene known to be important for inner ear prosensory development. Together, our results demonstrate that Sox10 regulates the biology of early cochlear progenitors during inner ear development, but, in contrast to neural crest-derived cells, this transcription factor is dispensable for their differentiation. Evidence also suggests that this effect occurs via the activation of the Jagged1 gene. [less ▲]

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See detailEarly identification of inner pillar cells during rat cochlear development.
Thelen, Nicolas ULg; Breuskin, Ingrid ULg; Malgrange, Brigitte ULg et al

in Cell & Tissue Research (2009), 337(1), 1-14

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Here, we examine its spatio-temporal development ... [more ▼]

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Here, we examine its spatio-temporal development in rats from embryonic day 16 (E16) to E19 by using cytochemical and immunocytochemical methods at the light- and electron-microscope levels. We demonstrate that the organ of Corti develops from a non-proliferating cell zone that is located in the junctional region between two edges of the dorsal epithelium of the cochlear duct. We also reveal that the first cells to develop in this zone are the inner pillar cells, a particular type of non-sensory supporting cell, which arise in the base of the cochlear duct at the boundary between the two ridges at E16. Cell differentiation in this prosensory region continues according to a base-to-apex gradient; the inner hair cells appear in the greater epithelial ridge at E17 and the outer hair cells in the lesser epithelial ridge at E18. At E19, the various cell types of the organ of Corti are in place. Finally, we show that unlike the development of all the supporting cell types of the organ of Corti, the development of inner pillar cells within the prosensory domain seems not to involve Notch1 activation. These results highlight the central role that the inner pillar cells probably play in the development of the organ of Corti. [less ▲]

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