The aim of the studies included in the thesis is to better understand the interplay between neuronal activity-dependent gene regulation and the bioactive vitamin A metabolite all-trans-retinoic acid (RA) during postnatal development, refinement and maintenance of precise neuronal connectivity using the olfactory sensory neuron (OSN) in the olfactory epithelium (OE) of genetically modified mice as a model. We show that: Inhibition of RA receptor (RAR)-mediated transcription in OSNs reduces expression of the olfactory cyclic nucleotide-gated (CNG) ion channel, which is required for odorant receptor (OR)-mediated stimulus transduction. This, results in increased OSN death and errors in precise connectivity. The increased cell death may be a consequence of reduced intrinsic excitability and/or reduced influx of Ca2+ ions while the errors in connectivity may be due to altered OR-dependent expression of axonal guidance proteins, such as Kirrel-2 and Neuropilin-1. Expression of the RA catabolic enzyme Cyp26B1 in OSNs is positively regulated by RAR-mediated transcription as well as sensory stimulation in a CNG channel-dependent manner. This shows that neuronal activity and local vitamin A metabolism are parts of novel regulatory feedback loop controlling precise connectivity and neuronal survival. The feedback loop may be a form of homeostatic plasticity in response to global changes in neuronal activity. BACE1, an enzyme is implicated in Alzheimer´s disease, and Cyp26B1 are inversely regulated by CNG channel-dependent sensory stimulation. Cyp26B1 expression is switched on at birth, forms a topographic expression gradient in OE and inhibits BACE1 expression into an inverse counter gradient. Taken together these results reveal a novel neuronal activity-dependent mechanism by which sensory stimuli can shape spatial gene expression via altered RA bioavailability. Increased Cyp26B1 expression stimulates turnover of OSNs during adult neurogenesis by a non-cell-autonomous mechanism. The gradient of Cyp26B1 expression correlates with spatially-regulated diversification of OSNs into subpopulations that express different subsets of OR genes. Cyp26B1 expression influences spatial OR diversification of OSNs by two different mechanisms. In the ventrolateral OE, Cyp26B1 inhibits OR expression by blocking OSN differentiation at a stage that may be associated with the cell intrinsic mechanism regulating OR gene choice. In the dorsomedial OE the expression frequency of some ORs is unaltered while other increases, presumably as a consequence of neuronal activity-dependent competition. A probable function of graded and activity-dependent Cyp26B1 expression is to form a topographic partitioning of the olfactory sensory map into functional domains, which gradually differ from each other with regard to experience-driven plasticity and neurogenic potential along the dorsomedial-ventrolateral axis of OE.

Au cours des dernières décennies, une dégradation de la fertilité des vaches laitières, parallèlement à une augmentation de la production laitière a été observée. Des régions du génome, les QTL, affectent la fertilité femelle. Le but de ce travail de thèse est d’étudier la fertilité et certains paramètres zootechniques chez des vaches Prim'Hosltein en première lactation choisies pour leur haplotype favorable "fertil+" ou défavorable "fertil-" pour un QTL de fertilité situé sur le chromosome 3. Ce phénotypage a montré une meilleure fertilité et un meilleur bilan énergétique dans la première semaine de lactation pour les vaches "fertil+" par rapport aux vaches "fertil-". De plus, les vaches "fertil-" ont un flux d’ingestion plus rapide. Au pic de mobilisation, certains gènes du QTL étaient différentiellement exprimés dans le tissu adipeux des deux haplotypes. Dans les cellules de la granulosa, un de ces gènes, nommé Kirrel, est plus exprimé chez les vaches "fertil+" et sa protéine recombinante inhibe la sécrétion de progestérone in vitro. Notre travail a permis d'affiner les interactions génotype-phénotype liées à un QTL de fertilité et de mettre en avant un des possibles rôles d'un gène de ce QTL dans la fonction de reproduction chez la vache laitière. / In recent decades, the dairy cow fertility has declined, in parallel with an increase in milk production. Some regions of the genome, named QTL, affect female fertility. The purpose of this thesis is to study fertility and some zootechnical parameters in Prim'Hosltein cows in first lactation chosen for their favorable haplotype "fertil+" or unfavorable haplotype "fertil-" for one fertility QTL on chromosome 3. This phenotyping showed better fertility and energy balance in the first week of lactation for "fertil+" than for "fertil-" cows. In addition, "fertil-" cows had a higher eating rate. At the peak of mobilization, the QTL genes are differentially expressed in adipose tissue of "fertil+" and "fertil-" cows. In granulosa cells, one of these genes, named Kirrel, is higher expressed in "fertil+" cows and its recombinant protein inhibits the secretion of progesterone in vitro. Our work has contributed to refine interactions genotype-phenotype linked to one fertility QTL and highlighted one of the possible roles of a gene which belongs to this QTL in the reproductive function in dairy cows.