La crête neurale (CN) est une population transitoire de cellules multipotentes qui émerge à la frontière entre l’ectoderme neural et non-neural, dans une région appelée la bordure neurale (BN). Lorsque la BN se soulève pour former le tube neural, les cellules de la CN subissent une transition épithélium-mésenchyme (TEM), et migrent de façon intensive dans l’ensemble de l’embryon pour atteindre leur destination finale et se différencier. Elles sont à l’origine de nombreux types de dérivés : neurones, cellules gliales, cartilage de la tête, os et tissus connectifs, cellules pigmentaires, cellules sympatho-adrenales. Tous ces processus sont régulés par l’action coordonnée de nombreux gènes qui forment un réseau de régulations génétiques complexe, au sein duquel de nombreuses interactions ont été décrites, même si de nombreuses relations restent à élucider à ce jour. Une mauvaise régulation de gènes normalement impliqués dans la formation de la CN provoque des malformations congénitales appelées neurocristopathies. Par ailleurs, la TEM subie par les cellules de CN avant leur migration est également observée dans les cellules cancéreuses acquérant des propriétés métastatiques. Les événements moléculaires et de nombreux gènes impliqués dans la TEM sont communs au développement de la CN et au cancer.Les liens existant entre le développement de la CN et les neurocristopathies, ainsi que les métastases, soulignent l’importance de l’étude du réseau de régulations génétiques permettant la formation de la CN et l’EMT.Au laboratoire, nous nous intéressons aux événements précoces d’induction et de spécification de la CN. Dans le but d’identifier les gènes préférentiellement impliqués dans le développement précoce de la CN et non dans la formation de l’ectoderme neural et non-neural, un crible a été effectué sur le transcriptome de différents tissus embryonnaires micro-disséqués. La validation des résultats de ce crible a permis d’identifier plusieurs gènes intéressants possédant une fonction potentielle dans la formation de la CN. Nous nous sommes particulièrement intéressés à deux d’entre eux, en raison de leur fonction originale comparée à la majorité des gènes impliqués dans le développement de la CN : serca1 et pfkfb4, un régulateur de l’homéostasie calcique et un régulateur de la glycolyse respectivement.Nous avons analysé les patrons d’expression des gènes des familles serca et pfkfb au cours du développement de Xenopus laevis. En raison de son expression spécifique dans la CN, nous avons étudié plus en détails le rôle de pfkfb4 dans la formation de la CN. Cette analyse a montré que pfkfb4 est nécessaire pour la spécification neurale et de la crête neurale.Toutefois, malgré son rôle documenté dans la glycolyse, le phénotype des morphants pfkfb4 dans l’embryon de Xenopus laevis n’est pas dû à une altération de la glycolyse.En conclusion, nos résultats démontrent l’existence d’un nouveau rôle non glycolytique pour Pfkfb4 au cours du développement embryonnaire de Xenopus Laevis. / Neural Crest (NC) is a transient population of multipotent cells that arises at the border between neural and non-neural ectoderm, in a region named the neural border (NB). As the neural border elevates to form the neural tube, NC cells undergo an Epithelial-To-Mesenchymal Transition (EMT), migrate extensively into the whole body to reach their final destinations and differentiate. They give rise to multiple derivatives: neurons and glia, head cartilage, bones and connective tissue, pigment cells, sympatho-adrenal cells. All these processes are regulated by the concerted actions of several genes that form a complex Gene Regulatory Network (GRN), in which many interactions have been elucidated, but even more relationships still need to be understood. Misregulation of genes normally involved in NC formation causes birth defects called neurocristopathies. Moreover, the EMT that NC cells undergo before migration also takes place when cancer cells become metastatic: the molecular events and many of the genes involved in EMT and migration are shared between NC development and cancer. The links with metastasis, neurocristopathies and the fact that still little is known about the earliest steps of NC formation, highlight the importance and the interest in understanding the Gene Regulatory Network (GRN) leading to NC formation and EMT.In the laboratory, we are interested in the early steps of NC induction and specification. In order to identify genes preferentially involved in early NC development compared to genes involved in neural and non-neural ectoderm formation, a transcriptome screen on different microdissected embryonic tissues has been performed. The validation of the results of the screen revealed several interesting genes with a potential function in NC formation. We focused particularly on two of them, due to their original function compared to the majority of the genes involved in NC development: serca1 and pfkfb4, a calcium homeostasis regulator and a glycolysis regulator respectively. We analysed the expression patterns of serca and pfkfb family genes during Xenopus laevis development. Then, due to its specific expression in NC, we studied more in details the role of pfkfb4 in NC formation. This analysis revealed that pfkfb4 is necessary for neural and neural crest specification. However, despite its known role in glycolysis, pfkfb4 morphant phenotype in Xenopus laevis embryos is not due to an alteration of the glycolytic pathway.In conclusion, our results reveal a novel extra-glycolytic role for Pfkfb4 during Xenopus laevis embryonic development.

Deux des trois divisions du système nerveux viscéral – le système nerveuxparasympathique et le système nerveux entérique – sont associés aux nerfscrâniens (le troisième, le système nerveux sympathique, est associé aux nerfsspinaux). Cette étude est centrée sur les nerfs crâniens et sur les ganglionsqui leur sont associés ; plus précisément sur les stratégies cellulaires ayantlieu lors de leur ontogenèse.Je propose des principes unificateurs concernant les interactions neuronalesmises en jeu lors de la formation des nerfs crâniens branchiomériques ainsiqu’un nouveau mode de migration des précurseurs des ganglionsparasympathiques couplé à la migration de leurs partenairespréganglionnaires jusqu’au site de formation du ganglion. Enfin, je présentecertaines observations préliminaires suggérant que les précurseurs dusystème nerveux entériques utilisent ce même modus operandi pour envahirl’oesophage. / Two of the three divisions of the visceral nervous system —theparasympathetic and the enteric nervous systems— are associated withcranial nerves (the third one, the sympathetic division, being associatedwith spinal nerves). This work is focused on cranial nerves and associatedganglia and more particularly on the cellular strategies presiding over theirontogeny and wiring.I propose unifying principles of neuronal interactions that govern theformation of branchiomeric cranial nerves, as well as a novel migrationpathway followed by parasympathetic precursors, which use theirpreganglionic nerves to migrate to the site of ganglion formation. Finally, Ipresent preliminary observations suggesting that the enteric neuronalprecursors use the same trick to populate the esophagus.

In this study, the origin and development of the intrinsic innervation in the foetal mouse lung is described and experimental evidence is provided to support the involvement of glial cell line-derived neurotrophic factor (GDNF) in the guidance of nerves and neuronal precursors in the developing lung. Antibodies were used to stain for neuronal precursors, neurones, nerve fibres, primordial epithelium and smooth muscle. These structures were revealed in whole mounts of foetal mouse lungs by immunofluorescence and confocal microscopy, and their spatial and temporal distribution was mapped from the onset of lung development and through the pseudoglandular period. The results showed that neuronal precursors, positive for neural crest cell markers, were present in the vagal tract of the foregut at embryonic day 10 (E10), the time of the evagination of the lung buds. These neural crest-derived cells (NCC) migrated into the lung at E11, along nerve processes directed from the vagus to the smooth musclecovered trachea and emerging lobar bronchi. During E11-E14, a network of nerves and ganglia became established along the dorsal trachea, and large ganglia formed a plexus at the ventral hilum. Nerve trunks issued from these ganglia, travelled along the smooth muscle-covered bronchi, providing a pathway for migrating NCC. To investigate the role of GDNF in the innervation of the lung, an in vitro model of left lung lobes was established. Lung growth and tubule branching was comparable to that in vivo, and neural tissue and smooth muscle continued to grow and thrive. A significant increase in nerve growth occurred when explants were cultured with GDNF compared to controls. Nerves extended, and NCC migrated towards GDNF-impregnated beads suggesting that GDNF may be the molecule guiding nerve fibres and NCC in the lung. The migrating NCC were negative for GDNF-family receptor α1 (GFRα1) during their migration into the lung while the nerves were positive. Since GDNF needs to be associated with its binding receptor, GFRα1, for cellular signalling, GDNF may induce the migration of the NCC if they migrate along the GFRα1-positive nerve fibres. It is concluded that neural tissue and smooth muscle become integral components of the lung shortly after the onset of lung development. The results show that the migration of neural crest-derived cells into the lung and the establishment of the innervation requires coordinated cross-talk between NCC, nerves and smooth muscle throughout development.

L'Est valentinois et le bassin de Crest constituent une partie de la moyenne vallée du Rhône séparant le Massif Central des Alpes ; cette dépression synclinale à coeur miocène orientée N- S, est largement recouverte d'alluvions quaternaires. L' étude sédimentologique des dépôts détritiques néogènes permet d'une part , de souligner le rôle primo dial joué par les apports alpins dans le remplissage du bassin et d'autre part , de retracer la paléogéographie de la région . La transgression débute au Burdigalien dans le bassin de Crest ; au cours du Langhien la mer gagne progressivement l'ensemble de la plaine de Valence . Au Tortonien supérieur ,le régime devient continental puis, après une intense érosion messinienne, une nouvelle ingression marine pliocène envahit les paléo vallées du Rhône et de ses affluents. L'étude hydrogéologique constitue une première approche globale de caractérisation de l'aquifère molassique . La connaissance précise du contexte géologique amène à la proposition d'un schéma simple du magasin aquifère. Une esquisse de la piézométrie a été dressée . l'estimation des paramètres hydrodynamiques permet de différentier la nappe superficielle circulant dans les alluvions quaternaires de la nappe profonde circulant dans les sables molassiques . L'hétérogénéité, tant verticale qu'horizontale est manifeste et l'étude géochimique confirme l'existence d'une stratification de I'aquifère miocène. La nappe est principalement alimentée par le toit , par infiltration des pluies efficaces . D'autres modes d' alimentation possibles sont envisagés .

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Distortion-based crest factor reduction (CFR) algorithms were studied in orthogonal frequency division multiplexing (OFDM) and multiple-input multiple-output (MIMO) OFDM systems to reduce the nonlinear distortion and improve the power efficiency of the transmitter front-end. First, definitions of peak-to-average-power ratio (PAR) were clarified based on the power efficiency improvement consideration in the MIMO-OFDM systems. Next, error vector magnitude (EVM) was used as the in-band performance-evaluating metric. Statistical analysis of EVM was performed to provide concrete thresholds for the amount of allowable distortions from each source to meet EVM requirements in the standard. Furthermore, an effective CFR technique, constrained clipping, was proposed to drastically reduce the PAR while satisfying any given in-band EVM and out-of-band spectral mask constraints. Constrained clipping has low computational complexity and can be easily extended to the multiple-user OFDM environment. Finally, signal-to-noise-and-distortion ratio (SNDR) analysis for transceiver nonlinearities in the additive white Gaussian noise channel was investigated. An analytical solution was presented for maximizing the transceiver SNDR for any given set of nonlinear transmitter polynomial coefficients. Additionally, mutually inverse pair of transceiver nonlinearities was shown to be SNDR-optimal only in the noise-free case.

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Type 1 diabetes develops through the progressive destruction of the insulin-producing beta-cells. Regeneration or replacement of beta-cells is therefore needed to restore normal glucose homeostasis. Presently, normoglycemia can be achieved by the transplantation of whole pancreas or isolated islets of Langerhans. Islet transplantation can be performed through a simple laparoscopic procedure, but the long-term graft survival is low due to poor revascularization and early cell death. This thesis examined the possibility of using different auxiliary cells (Schwann cells, endothelial progenitor cells, and neural crest stem cells) to improve the engraftment and function of endogenous and transplanted islets. Co-transplantation of Schwann cells with islets improved islet graft function early after transplantation, and caused an increased islet mass at one month posttransplantation. However, the vascular densities of these grafts were decreased, which also related to an impaired graft function. Islet grafts containing endothelial progenitor cells had a superior vascular density, with functional chimeric blood vessels and substantially higher blood perfusion and oxygen tension than control transplants. By culturing and transplanting islets together with neural crest stem cells it was found that islets exposed to these cells had a higher beta-cell proliferation compared with control islets. At one month posttransplantation, the grafts with neural crest stem cells also had a superior vascular- and neural density. The potential of intracardially injected neural crest stem cells to home to the pancreas and ameliorate hyperglycemia in diabetic mice was investigated. During a three-week period after such cell treatment blood glucose concentrations decreased, but were not fully normalized. Neural crest stem cells were present in more than 10% of the pancreatic islets at two days postinjection, at which time the beta-cell proliferation was markedly increased when compared with islets of saline-treated diabetic animals. Three weeks later, a doubled beta-cell mass was observed in animals receiving neural crest stem cells. In summary, islets can easily be transplanted together with different auxiliary cells. Some of these cells provide the possibility of improving vascular- and neural engraftment, as well as beta-cell growth and survival. Systemic administration of neural crest stem cells holds the potential of regenerating the endogenous beta-cells.