Unravelling the roles of lysine acetylation by Elp3 during inner ear development

Poster (2013, January 28)

The inner ear is composed of the vestibular system that controls balance, and the cochlea, which is dedicated to hearing. In both parts of the inner ear, sensory epithelia comprise supporting cells ... [more ▼]

The inner ear is composed of the vestibular system that controls balance, and the cochlea, which is dedicated to hearing. In both parts of the inner ear, sensory epithelia comprise supporting cells surrounding the sensory hair cells. These cells bear at their apical surface a staircase-structured bundle, consisting of multiple rows of actin-based stereocilia and a single tubulin-based kinocilium. This hair bundle allows the transduction from mechanical stimuli, initiated by sound or gravitational changes, to electrical signals that will then be transmitted by neurons from the spiral ganglion (innervating hair cells of the cochlea) or the vestibular ganglion. The inner ear organogenesis requires a tightly regulated transcriptional program that can be affected by post-transcriptional and post-translational modifications among which lysine acetylation. Given the importance of acetylation homeostasis in controlling developmental processes, we planned to investigate its role in inner ear formation and focused our attention on Elp3 acetyl-transferase, a member of the Elongator complex recently implicated in neurogenesis. To determine the role of Elp3 in the inner ear, we first determine the spatio-temporal pattern of ELp3 mRNA expression and showed that it was expressed in the entire early otocyst at E11.5 and persisted later in the sensory epithelium of the cochlea (the organ of Corti), in the spiral ganglion, in the stria vascularis and in the vestibule. To unravel in vivo functions of Elp3 in the inner ear, we have generated conditional knock-out mice (Elp3 cKO). We submitted these mice to a battery of vestibular testing (i.e. stereotyped circling ambulation, head bobbing, retropulsion, and absence of reaching response in the tail-hanging test) and found significant abnormalities. Besides, compared to wild-type mice, the auditory brain stem response of Elp3 cKO indicated that these mice are severely deaf. At the cellular level, we did not found any structural abnormalities nor cell patterning impairments that could explain deafness or balance dysfunction in Elp3 cKO mice. However, we detected some defaults in the planar orientation of their auditory hair cell bundle. In addition, the length of the kinocilium was significantly reduced both in vestibular and cochlear hair cells from Elp3 cKO mice compared with wild type littermates. We were also able to demonstrate an increased level of apoptosis in the Elp3 cKO spiral ganglion at E14.5 leading to a reduced number of fibers innervating the cochlear hair cells as well as a reduced number of their synaptic ribbons at P0 and P15. In conclusion, our results clearly showed a role of Elp3 both in hearing and balance. We plan to go deeper in the mechanisms involved through the identification of the proteins acetylated by Elp3. [less ▲]

Gene transfer in inner ear cells: a challenging race

in Gene Therapy (2012)

Recent advances in human genomics led to the identification of numerous defective genes causing deafness, which represent novel putative therapeutic targets. Future gene-based treatment of deafness ... [more ▼]

Recent advances in human genomics led to the identification of numerous defective genes causing deafness, which represent novel putative therapeutic targets. Future gene-based treatment of deafness resulting from genetic or acquired sensorineural hearing loss may include strategies ranging from gene therapy to antisense delivery. For successful development of gene therapies, a minimal requirement involves the engineering of appropriate gene carrier systems. Transfer of exogenous genetic material into the mammalian inner ear using viral or non-viral vectors has been characterized over the last decade. The nature of inner ear cells targeted, as well as the transgene expression level and duration, are highly dependent on the vector type, the route of administration and the strength of the promoter driving expression. This review summarizes and discusses recent advances in inner ear gene-transfer technologies aimed at examining gene function or identifying new treatment for inner ear disorders. [less ▲]

Cycling or not cycling: cell cycle regulatory molecules and adult neurogenesis.

in Cellular and Molecular Life Sciences : CMLS (2012), 69(9), 1493-1503

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs ... [more ▼]

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain. [less ▲]

Comparaison des outils bibliographiques et bibliométriques Web of Science et Scopus : rapport du groupe de réflexion mis en place par la Bibliothèque Interuniversitaire de la Communauté française de Belgique (BICfB)

Report (2011)

Depuis 2002, l'ensemble des membres de la BICfB souscrivent au Web of Science (WoS) de Thomson Reuters, plus précisément aux sous-bases Science Citation Index (SCI), Social Sciences Citation Index (SCCI ... [more ▼]

Depuis 2002, l'ensemble des membres de la BICfB souscrivent au Web of Science (WoS) de Thomson Reuters, plus précisément aux sous-bases Science Citation Index (SCI), Social Sciences Citation Index (SCCI) et Arts and Humanities Citation Index (A&HCI). Web of Science, partie du Web of Knowledge (WoK), est une base de données bibliographiques et d'analyse de citations renommée, au départ unique en son genre. Avec le Journal Citation Reports (JCR), elle est également beaucoup utilisée comme base de référence dans l'évaluation des chercheurs et de la recherche. En 2004, deux ressources concurrentes ont vu le jour. Il s'agit de Google Scholar (gratuit mais n'offrant pas autant de fonctionnalités) et de Scopus, un produit Elsevier. Aussi, lors de l'Assemblée générale de la BICfB du 4 mai 2010, les institutions ont décidé de constituer un groupe de réflexion interuniversitaire composé de membres issus des conseils ou administrations de la recherche, de bibliothèques et de représentants du F.R.S.-FNRS afin de comparer en profondeur ces outils. Ce rapport, présenté lors de l'AG du 7 juin 2011 de la BICfB, est le fruit du travail du groupe de réflexion. [less ▲]

Distribution of glycogen during the development of the organ of Corti

Poster (2011, January 31)

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Using cytochemical methods at the light and ... [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. Using cytochemical methods at the light and electron microscope levels, we examined the spatiotemporal distribution of polysaccharides during the development of the organ of Corti in rats from embryonic day 16 (E16) to postnatal day 15 (P15). At E16, small polysaccharide inclusions were detected in the cytoplasm of the future inner pillar cells by electron microscope only. These inclusions became obvious at the light microscope level at E17. At E19, the polysaccharide deposits were important within the inner pillar cells and they arose in the Hensen cells cytoplasm. Polysaccharide accumulations also appeared in the outer pillar cells and the Deiters cells from P3-P4. As the organ of Corti developed, the amount of polysaccharide inclusions within the inner and outer pillar cells decreased. At P15, large amount of polysaccharide deposits were visible in the Deiters cells whereas they had almost disappeared from the inner and outer pillar cells. Finally, we showed that the polysaccharide deposits present in the developing organ of Corti are PAS-positive and can be digested with a salivary amylase, suggesting that they are essentially constituted of glycogen. [less ▲]

Cdk6-dependent regulation of g(1) length controls adult neurogenesis.

in Stem Cells (2011), 29(4), 713-24

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here ... [more ▼]

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G(1) regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G(1) phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G(1) length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM Cells 2011;29:713-724. [less ▲]

Structure and development of cochlear afferent innervation in mammals.

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 ▲]

Glial but not neuronal development in the cochleo-vestibular ganglion requires Sox10.

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 ▲]

Ototoxic drugs: difference in sensitivity between mice and guinea pigs.

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 ▲]

Hair cell progenitors: identification and regulatory genes

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 ▲]