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Some fungi have been domesticated for food production, with genetic differentiation between populations from food and wild environments, and food populations often acquiring beneficial traits through horizontal gene transfers (HGTs). Studying their adaptation to human-made substrates is of fundamental and applied importance for understanding adaptation processes and for further strain improvement. We studied here the population structures and phenotypes of two distantly related Penicillium species used for dry-cured meat production, P. nalgiovense, the most common species in the dry-cured meat food industry, and P. salamii, used locally by farms. Both species displayed low genetic diversity, lacking differentiation between strains isolated from dry-cured meat and those from other environments. Nevertheless, the strains collected from dry-cured meat within each species displayed slower proteolysis and lipolysis than their wild conspecifics, and those of P. nalgiovense were whiter. Phenotypically, the non-dry-cured meat strains were more similar to their sister species than to their conspecific dry-cured meat strains, indicating an evolution of specific phenotypes in dry-cured meat strains. A comparison of available Penicillium genomes from various environments revealed HGTs, particularly between P. nalgiovense and P. salamii (representing almost 1.5 Mb of cumulative length). HGTs additionally involved P. biforme, also found in dry-cured meat products. We further detected positive selection based on amino acid changes. Our findings suggest that selection by humans has shaped the P. salamii and P. nalgiovense populations used for dry-cured meat production, which constitutes domestication. Several genetic and phenotypic changes were similar in P. salamii, P. nalgiovense and P. biforme, indicating convergent adaptation to the same human-made environment. Our findings have implications for fundamental knowledge on adaptation and for the food industry: the discovery of

Chemerin, the product of tazarotene-induced gene 2 (TIG2) or retinoid acid receptor responder 2 (RARRES2), was originally identified in our laboratory as the natural ligand of the Chemokine like receptor 1 (CMKLR1), also known as ChemR23 or Chemerin1. This potent chemoattractant factor (for macrophages, dendritic cells and natural killer cells) and adipokine appears to regulate leukocyte trafficking, inflammatory responses, angiogenesis and metabolism. In line with this, chemerin was reported to be implicated in various chronic inflammatory diseases, as well as in obesity and obesity-related diseases, such as type 2 diabetes mellitus and cardiovascular diseases. Furthermore, work performed on murine melanoma models in our group and by others highlighted the tumor-suppressive properties of chemerin in various cancer types, although the precise mechanisms by which chemerin acts on tumor initiation and/or progression is still poorly understood, with conflicting results, especially in melanoma. In this project, we sought to use the unique strengths of the zebrafish model system in combination with state-of-the-art techniques to address this question. In recent years, the zebrafish (Danio rerio) has emerged as a powerful model system for the study of cancer and immune cell biology in ways not possible in other vertebrates. Well established zebrafish cancer models in combination with the availability of various lineage-specific fluorescent transgenic reporter lines, offers unprecedented opportunities for high resolution in vivo analysis of cancer development and the dynamic interactions between tumor cells and the host microenvironment. A detailed characterization of the zebrafish chemerin system and its evolutionary history showed that the chemerin axis is highly conserved across the vertebrate phylum, although we found that zebrafish possesses more chemerin and Cmklr1 genes than mammalian species, due to several sequence duplication events. Subsequently, we generated kn, La chémérine, produit du gène tazarotene-induced gene 2 (TIG2) ou retinoid acid receptor responder 2 (RARRES2), a été initialement identifiée dans notre laboratoire comme le ligand naturel du récepteur Chemokine like receptor 1 (CMKLR1), également connu sous le nom de ChemR23 ou Chemerin1. Cette puissante molécule chimioattractante (pour les macrophages, cellules dendritiques et cellules tueuses naturelles) et adipokine est décrite comme régulant le trafic des leucocytes, les réponses inflammatoires, l'angiogenèse et le métabolisme. En ligne avec ces fonctions, la chémérine a été rapportée comme étant impliquée dans diverses maladies inflammatoires chroniques, ainsi que dans l'obésité, le diabète de type 2 et les maladies cardiovasculaires. En outre, les travaux réalisés sur des modèles murins de mélanome dans notre groupe et par d'autres ont mis en évidence les propriétés anti-tumorales de la chémérine dans divers types de cancer, bien que les mécanismes précis par lesquels la chémérine agit sur l'initiation et/ou la progression tumorale soient encore mal compris, avec des données contradictoires, en particulier dans le cas du mélanome. Dans ce projet, nous avons cherché à utiliser les atouts uniques du modèle poisson-zèbre, en combinaison avec des techniques de pointe, pour répondre à cette question. Ces dernières années, le poisson-zèbre (Danio rerio) est en effet devenu un modèle puissant pour l'étude du cancer et de la biologie des cellules immunitaires, avec des approches qui ne sont pas possibles chez les autres vertébrés. Des modèles de cancer bien établis chez le poisson-zèbre, combinés à la disponibilité de diverses lignées transgéniques exprimant des rapporteurs fluorescents dans des populations cellulaires spécifiques, offrent des possibilités sans précédent d'analyse in vivo à haute résolution des stades de développement du cancer et des interactions dynamiques entre cellules tumorales et le microenvironnement de l'hôte. Une caractérisation détaillée du, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Angiogenesis is an essential and complex process, by which new blood vessels grow from preexisting ones, as a tightly regulated response of endothelial cells (ECs) to a combination of pro- and anti-angiogenic factors. The establishment of a functional blood vessel network is initiated by the formation of a primitive vascular plexus, from which new blood vessels sprout, coordinately expand, and branch. Redundant vessel branches are then selectively removed through vessel regression, a process called pruning.Chemerin was originally isolated from inflammatory exudate fluids and found to be a ligand for the orphan G protein-coupled receptor, ChemR23/CMKLR1. Active chemerin is a chemoattractant factor for immature dendritic cells, natural killer cells and macrophages, by acting through CMKLR1. Bioactive chemerin generation and infiltration by CMKLR1-expressing cells have been described in various human diseases. We and others have identified both pro- and anti-inflammatory activities of the chemerin/CMKLR1 system according to the experimental setting. Our laboratory reported the antitumor activity of chemerin in a chemical model of skin carcinogenesis, and more recently, in two tumor graft models. These anti-tumoral properties were reported as independent from leukocyte recruitment. Instead, a reduction of the neoangiogenesis process was identified as the driving mechanism explaining the delay in tumor growth.The role played by chemerin during angiogenesis remains controversial. Pro-angiogenic, but often moderate effects of chemerin were reported. In this thesis, we investigated the role of chemerin on the neonatal development of the retinal vascular network in mice, a well-established model. We used for this purpose a mouse line allowing the controlled overexpression of a bioactive form of chemerin in keratinocytes, which results in a significant increase of chemerin bioactivity in the whole body. We observed in these mice a reduction in the density of the retinal vascu, L'angiogenèse est la formation de nouveaux vaisseaux sanguins à partir des vaisseaux préexistants. L'établissement d'un réseau de vaisseaux sanguins fonctionnels est initié par la formation d'un plexus vasculaire primitif, à partir duquel de nouveaux vaisseaux sanguins se développent de manière coordonnée et se ramifient. Les branches de vaisseaux redondantes sont ensuite sélectivement supprimées par régression des vaisseaux, un processus appelé élagage.La chémérine est une protéine multifonctionnelle initialement caractérisée par le laboratoire hôte comme un facteur chimioattractant pour certaines populations de leukocytes. Son principal récepteur fonctionnel est ChemR23/CMKLR1. Notre groupe a identifié un mécanisme original par lequel la chémérine retarde la progression tumorale, en inhibant la vascularisation efficace des tumeurs et leur croissance. Le but de mon projet de thèse est d'étudier plus précisément comment la chémérine affecte l’angiogenèse, in vitro et in vivo, en utilisant un ensemble de modèles génétiques établis ou nouvellement développés chez la souris. Dans l'ensemble, nous visons à valider le système chémérine comme cible thérapeutique dans le cadre du cancer humain. Nous avons démontré que les souris surexprimant la chémérine développent en effet un réseau vasculaire rétinien moins dense, et cette particularité perdure jusqu’à l’âge adulte. Nous avons pu déterminer que ce n’est pas la formation du réseau qui est affectée, mais bien la stabilité des néovaisseaux lors de la phase de maturation de ce réseau. Il en résulte une nette augmentation de l’apoptose des cellules endothéliales et une régression accrue de segments vasculaires du réseau. L’expression de chémérine protège partiellement de l’angiogenèse excessive observée dans un modèle de rétinopathie, réduit le temps de récupération de la perfusion suite à la ligature de l’artère fémorale et perturbe distribution de collagène de type IV autour des cellules endothéliales, signe d’un manque de, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Polycystic ovarian syndrome (PCOS) is the main cause of infertility in women. It is frequently associated with reduced progesterone production by human luteinised granulosa cells (hlGCs). However, the molecular mechanisms involved in these steroidogenesis alterations in PCOS patients are unclear. In a dihydrotestosterone-induced PCOS mouse model, steroid production is maintained in the setting of chemokine-like receptor 1 (Cmklr1) knockout. Thus, chemerin and chemerin receptors in terms of expression and progesterone regulation could be different in control and PCOS hlGCs. We first confirmed that progesterone levels in both plasma (P < 0.0001) and follicular fluid (FF) (P < 0.0001) were significantly reduced in PCOS normal weight women compared to control women. These data were associated with a lower STAR mRNA expression in both in vivo (P < 0.0001) and in vitro (P < 0.0001) hlGCs from PCOS women. Secondly, chemerin FF levels (P < 0.0001) and RARRES2 (P < 0.05) and CMKLR1 (P < 0.0001) mRNA levels in GCs were higher in PCOS normal weight patients. Thirdly, treatment of hlGCs with a specific nanobody (the VHH CA4910) targeting the human receptor for CMKLR1 leading to its inactivation abolished chemerin-induced progesterone inhibition, suggesting the involvement of CMKLR1 in this process. Furthermore, the inhibition of progesterone secretion induced by chemerin was two-fold higher in PCOS hlGCs (P < 0.05). Moreover, the VHH CA4910 reinstated a normal progesterone secretion with lower concentrations in PCOS hlGCs, suggesting a different chemerin sensitivity between PCOS and control hlGCs. Thus, chemerin, through CMKLR1, could be involved in the steroidogenesis alterations in PCOS hlGCs., info:eu-repo/semantics/published