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Gustave Moonen

Publications and source records attributed to Gustave Moonen.

14 recordsLinked to original sources
PubMed2003

The inhibition of cyclin-dependent kinases induces differentiation of supernumerary hair cells and Deiters' cells in the developing organ of Corti.

In the embryonic day 19 organs of Corti, we showed that roscovitine, a chemical inhibitor of cyclin-dependent kinases (CDKs), significantly increased the number of hair cells (HCs) and corresponding supporting cells (SCs) by triggering differentiation of precursor cells without interacting with cell proliferation. The effect of roscovitine was mimicked by other CDK1, 2, 5, and 7 inhibitors but not by CDK4/6 and mitogen-activated protein kinase pathway antagonists. Immunohistochemical analysis indicated that roscovitine-specific intracellular targets, CDK1, 2, 5, and 7, were expressed in the organ of Corti and especially in Hensen's cells. Affinity chromatography studies showed a tight correlation between the protein levels of CDK1/2 and 5 and the rate of roscovitine-induced supernumerary cells in the organ of Corti. In addition, we demonstrated that basal CDK activity was higher and more roscovitine-sensitive at developmental stages that are selectively permissive for the emergence of supernumerary cells. These results suggest that CDKs are involved in the normal development of the organ of Corti and that, at least in E19 embryos, inhibition of CDKs is sufficient to trigger the differentiation of HCs and corresponding SCs, presumably from the Hensen's cell progenitors and/or from progenitors located in the greater epithelial ridge area.

Animals↗
PubMed2003

Autocrine/paracrine activation of the GABA(A) receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum.

GABA and its type A receptor (GABA(A)R) are present in the immature CNS and may function as growth-regulatory signals during the development of embryonic neural precursor cells. In the present study, on the basis of their isopycnic properties in a buoyant density gradient, we developed an isolation procedure that allowed us to purify proliferative neural precursor cells from early postnatal rat striatum, which expressed the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). These postnatal striatal PSA-NCAM+ cells were shown to proliferate in the presence of epidermal growth factor (EGF) and formed spheres that preferentially generated neurons in vitro. We demonstrated that PSA-NCAM+ neuronal precursors from postnatal striatum expressed GABA(A)R subunits in vitro and in situ. GABA elicited chloride currents in PSA-NCAM+ cells by activation of functional GABA(A)R that displayed a typical pharmacological profile. GABA(A)R activation in PSA-NCAM+ cells triggered a complex intracellular signaling combining a tonic inhibition of the mitogen-activated protein kinase cascade and an increase of intracellular calcium concentration by opening of voltage-gated calcium channels. We observed that the activation of GABA(A)R in PSA-NCAM+ neuronal precursors from postnatal striatum inhibited cell cycle progression both in neurospheres and in organotypic slices. Furthermore, postnatal PSA-NCAM+ striatal cells synthesized and released GABA, thus creating an autocrine/paracrine mechanism that controls their proliferation. We showed that EGF modulated this autocrine/paracrine loop by decreasing GABA production in PSA-NCAM+ cells. This demonstration of GABA synthesis and GABA(A)R function in striatal PSA-NCAM+ cells may shed new light on the understanding of key extrinsic cues that regulate the developmental potential of postnatal neuronal precursors in the CNS.

Animals↗
PubMed2003

Chemical inhibitors of cyclin-dependent kinases control proliferation, apoptosis and differentiation of oligodendroglial cells.

Since cyclin-dependent kinases (Cdks) and their endogenous inhibitors (Cdkis) play an essential role as regulators of cell cycle withdrawal and onset of differentiation within oligodendroglial cells, we assessed here the effects of exogenous chemical Cdk inhibitors (CKIs) on cultured rat cortical oligodendrocyte progenitor cells (OPCs). We showed that purine derivatives and especially roscovitine strongly inhibited OPCs proliferation. In the presence of mitogenic signals, roscovitine synergized with thyroid hormone to stimulate oligodendrocyte differentiation. Roscovitine also prevented oligodendroglial apoptosis induced by growth factor deprivation. We thus demonstrated that small molecular weight chemical CKIs have important effects on crucial events of oligodendroglial development in vitro. This might open prospects for using these apparently well tolerated agents in remyelination strategies.

Animals↗
PubMed2003

Effects of Alzheimer's disease on the recognition of novel versus familiar words: neuropsychological and clinico-metabolic data.

This study explored recognition memory performance for novel versus familiar words in Alzheimer's disease (AD) patients and normal controls (NCs), using an adaptation of E. Tulving and N. Kroll's (1995) procedure. Results showed that both groups exhibited more hits and more false alarms for familiar than for novel words. The groups did not differ in the recognition of familiar words, reflecting preserved familiarity processes in AD. However, AD patients made more false alarms than NCs in the recognition of novel words, reflecting impairment of recollection processes in AD. A positron emission tomography analysis of clinico-metabolic correlations in AD patients showed a correlation between recognition of novel words and right hippocampal activity, whereas recognition of familiar words was more related to metabolic activity in the left posterior orbitofrontal cortex.

Aged↗
PubMed2003

Untangling the functional potential of PSA-NCAM-expressing cells in CNS development and brain repair strategies.

Central nervous system (CNS) neural stem cells (NSCs), which are mostly defined by their ability to self-renew and to generate the three main cell lineages of the CNS, were isolated from discrete regions of the adult mammalian CNS including the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus in the hippocampus. At early stages of CNS cell fate determination, NSCs give rise to progenitors that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). PSA-NCAM(+) cells persist in adult brain regions where neuronal plasticity and sustained formation of new neurons occur. PSA-NCAM has been shown to be involved in the regulation of CNS myelination as well as in changes of cell morphology that are necessary for motility, axonal guidance, synapse formation, and functional plasticity in the CNS. Although being preferentially committed to a restricted either glial or neuronal fate, cultured PSA-NCAM(plus) progenitors do preserve a relative degree of multipotentiality. Considering that PSA-NCAM(+) cells can be neatly used for brain repair purposes, there is much interest for studying signaling factors regulating their development. With this regard, it is noteworthy that neurotransmitters, which belong to the micro-environment of neural cells in vivo, regulate morphogenetic events preceding synaptogenesis such as cell proliferation, migration, differentiation and death. Consistently, several ionotropic but also G-protein-coupled neurotransmitter receptors were found to be expressed in CNS embryonic and postnatal progenitors. In the present review, we outlined the ins and outs of PSA-NCAM(plus) cells addressing to what extent our understanding of extrinsic and in particular neurotransmitter-mediated signaling in these CNS precursor cells might represent a new leading track to develop alternative strategies to stimulate brain repair.

Animals↗
PubMed2002

Identification of factors that maintain mammalian outer hair cells in adult organ of Corti explants.

Both outer hair cells (OHCs) and inner hair cells (IHCs) survive and mature in 3 days old rat organ of Corti explants cultured for 1 month in a minimal essential medium. In contrast, under the same culture conditions, only IHCs survive in explants from adult guinea pig organ of Corti while many of the OHCs are lost within the first 48 h. Hair cell counts show OHCs loss to be greater in the lower portion (i.e. middle turn) of the cochlea than at the apex. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) indicates that there is DNA damage in adult OHCs within 8 h of explantation. Treatment of the adult organ of Corti explants with either actinomycin D (10(-7) M) or cycloheximide (10(-6) M) prevents most OHC losses. According to these results apoptosis may be the mechanism of OHC loss in adult organ of Corti explants. Stable membrane potentials recorded from the OHCs in both uncultured and actinomycin D-treated organ of Corti explants cultured for 72 h demonstrate the functional integrity of these hair cells. OHC losses in the adult guinea pig organ of Corti cultures can also be prevented by treatment with several of the growth factors tested, i.e. acidic fibroblast growth factor (aFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), and glial cell-derived neurotrophic factor (GDNF). The results of this study suggest that growth factor therapy may be applicable to the treatment of some hearing disorders.

Animals↗
PubMed2002

Proliferative generation of mammalian auditory hair cells in culture.

Hair cell (HC) and supporting cell (SC) productions are completed during early embryonic development of the mammalian cochlea. This study shows that acutely dissociated cells from the newborn rat organ of Corti, developed into so-called otospheres consisting of 98% nestin (+) cells when plated on a non-adherent substratum in the presence of either epidermal growth factor (EGF) or fibroblast growth factor (FGF2). Within cultured otospheres, nestin (+) cells were shown to express EGF receptor (EGFR) and FGFR2 and rapidly give rise to newly formed myosin VIIA (+) HCs and p27(KIP1) (+) SCs. Myosin VIIA (+) HCs had incorporated bromodeoxyuridine (BrdU) demonstrating that they were generated by a mitotic process. Ultrastructural studies confirmed that HCs had differentiated within the otosphere, as defined by the presence of both cuticular plates and stereocilia. This work raises the hypothesis that nestin (+) cells might be a source of newly generated HCs and SCs in the injured postnatal organ of Corti.

Animals↗
PubMed2002

Functional glycine receptors are expressed by postnatal nestin-positive neural stem/progenitor cells.

Multipotent neural stem and progenitor cells (NS/PCs) are well-established cell subpopulations occurring in the developing, and also in the mature mammalian nervous systems. Trophic and transcription factors are currently the main signals known to influence the development and the commitment of NS/PCs and their progeny. However, recent studies suggest that neurotransmitters could also contribute to neural development. In that respect, rodent-cultured embryonic NS/PCs have been reported to express functional neurotransmitter receptors. No similar investigation has, however, been made in postnatal and/or in adult rodent brain stem cells. In this study, using RT-PCR and immunocytochemical methods, we show that alpha(1)-, alpha(2)- and beta-subunit mRNAs and alpha-subunit proteins of the glycine ionotropic receptor are expressed by 80.5 +/- 0.9% of postnatal rat striatum-derived, nestin-positive cells within cultured neurospheres. Whole-cell patch-clamp experiments further demonstrated that glycine triggers in 33.5% of these cells currents that can be reversibly blocked by strychnine and picrotoxin. This demonstrates that NS/PCs express functional glycine receptors, the consequence(s) of their activation remaining unknown.

Animals↗
PubMed2002

Exploring the effect of action familiarity on SPTs recall performance in Alzheimer's disease.

This study examined the performance of normal controls (NC) and Alzheimer's disease (AD) patients on free recall, semantic cued recall and object cued recall of both subject-performed tasks (SPTs) and verbal descriptions of actions, by controlling familiarity of actions associated to objects. The results showed that both groups performed better after SPT encoding than after verbal encoding, in all three types of recall. In addition, this SPT advantage was greater for AD patients than for NC in the object cued recall test, emphasizing AD patients' sensibility to the congruence of cues between encoding and retrieval conditions. Following verbal encoding, NC showed a better recall for less familiar actions than for highly familiar actions, whereas AD patients exhibited the opposite pattern. These results reflect that AD patients did not benefit from a distinctiveness effect at encoding for improving subsequent retrieval of verbal information, probably due to a reduced level of elaboration during encoding. However, there was no effect of action familiarity on recall performance by both groups following SPT encoding. These results suggest that memory for verbal actions and SPTs is governed by different principles. In addition, they demonstrate the robustness of the SPT effect in AD patients, who were able to improve memory performance in the SPT condition not only with highly familiar actions but also with less familiar actions.

Aged↗
PubMed2002

Brain function in the vegetative state.

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.

Cerebral Cortex↗
PubMedDate not supplied

Brain correlates of performance in a free/cued recall task with semantic encoding in Alzheimer disease.

The goal of this study was to explore in patients with Alzheimer's disease (AD) the brain correlates of free and cued recall performance using an adaptation of the procedure developed by Grober and Buschke (1987). This procedure, which ensures semantic processing and coordinates encoding and retrieval, has been shown to be very sensitive to an early diagnosis of AD. Statistical parametric mapping (SPM 99) was used to establish clinicometabolic correlations between performance at free and cued verbal recall and resting brain metabolism in 31 patients with AD. Results showed that patient's score on free recall correlated with metabolic activity in right frontal regions (BA 10 and BA 45), suggesting that performance reflected a strategic retrieval attempt. Poor retrieval performance was tentatively attributed to a loss of functional correlation between frontal and medial temporal regions in patients with AD compared with elderly controls. Performance on cued recall was correlated to residual metabolic activity in bilateral parahippocampal regions (BA 36), suggesting that performance reflected retrieval of semantic associations, without recollection in AD. In conclusion, this study demonstrates that the diagnostic sensitivity for Alzheimer's disease of the cued recall performance in the Grober and Buschke procedure (1987) depends on the activity of parahippocampal regions, one of the earliest targets of the disease. Moreover, the results suggest that the poor performance of patients with AD during free and cued recall is related to a decreased connectivity between parahippocampal regions and frontal areas.

Aged↗
PubMedDate not supplied

Mechanisms of cell death in the injured auditory system: otoprotective strategies.

Oxidative stress insults such as neurotrophin withdrawal, sound trauma, hypoxia/ischemia, ototoxic antibiotics, and chemotherapeutic agents have been shown to induce apoptosis of both auditory hair cells and neurons. In this paper, we review some components of the apoptotic pathways leading to the death of hair cells and auditory induced by growth factor withdrawal or cisplatin intoxication: (1) reactive oxygen species and free radicals are formed as by-products of several metabolic pathways and these molecules can themselves cause cell damage by reacting with cellular proteins; (2) activation of caspases, and (3) activation of calpain. These mechanisms have several different points at which inhibitors could be targeted to protect cells from programmed cell death, including the prevention of oxidative stress-induced apoptosis and the activation of caspases and calpains.

Animals↗