The B cell population is one of the key components of the adaptive immune system, which protects the host from a tremendous variety of pathogens by producing antibodies. B cells develop from hematopoietic stem cells through a pathway known as B lymphopoiesis. This is a process accompanied by intensive gene expression reprogramming. By the end, genes appropriate for the B lineage are activated and those that are not are continuously repressed. The regulation of lineage gene expression is conferred by a network of transcriptional regulators. Although some key components have been defined, more factors, especially those orchestrating the repression of non-B lineage genes, remain to be identified. Chemically induced mutagenesis is a potent way of identifying genes with critical biological functions. Injection of n-ethyl-n-nitrosourea, a mutagen, has generated a unique point mutation in the mouse Gon4-like (Gon4l) gene that specifically causes a loss of peripheral B cells while maintaining the T cell population. The mutation is therefore named Justy for Just T cells. The goal of this thesis project is to analyze the Justy mice and provide insights into the mechanisms underlying the regulation of B lymphopoiesis. The work presented here demonstrates that the protein encoded by Gon4l is essential for early B lymphopoiesis, which is likely through the repression of non-B lineage genes. Gon4l protein contains conserved domains implicated in transcriptional repression and associates in a complex with the transcriptional repression mediators Yin Yang 1 and Sin3a/HDAC1, after these proteins are transiently expressed in cell lines. When bound to DNA, Gon4l is capable of repressing a nearby promoter and this function correlates with its ability to form a complex. Therefore, these results suggest that Gon4l may function as a transcriptional regulator by employing its associated co-factors in the identified complex. Lastly, a wide spectrum of tumors developed in Justy mice, indicating that Gon4l can also act as a tumor suppressor.

Les CSH sont responsables de la production de toutes les cellules sanguines et possèdent une double capacité d'auto-renouvellement et de différenciation en progéniteurs incluant les progéniteurs lymphoïdes B. Étant donné l’importance des CSH, leur physiologie est étroitement contrôlée par une pléthore de signaux qui équilibrent quiescence, prolifération, auto-renouvellement et différenciation. La diminution de la fonction des CSH au cours du vieillissement dépend de plusieurs facteurs intrinsèques et extrinsèques, y compris l’accumulation des ROS au cours du vieillissement. Lorsque les taux de ROS intracellulaires deviennent excessifs, ils provoquent une sénescence ou une apoptose, entraînant un épuisement prématuré des CSH et un dysfonctionnement hématopoïétique. La régulation et les effets des ROS sont donc liés au destin des CSH. Notre laboratoire a dévoilé l'activité antioxydante de la protéine TP53INP1. En effet, les souris KO développent un stress oxydatif chronique. Le gène codant pour TP53INP1 est exprimé au niveau basal dans tous les types de cellules de la MO et est fortement surexprimé lorsque la moelle osseuse lors du vieillissement. L'analyse des compartiments cellulaires de la MO a montré que l'absence de TP53INP1 a un impact important sur la différenciation des cellules B, qui est étonnamment maintenue dans la moelle osseuse des souris KO âgées, et réduite chez les souris WT âgées. Ces cellules B produisent IgM et IgG et sont fonctionnelles. Le traitement antioxydant inverse le phénotype observé. Enfin, nous démontrons que la maintenance des lymphocytes B chez les souris KO âgées est dépendant de la voie de signalisation IL-7Rα / pSTAT5. / HSCs are responsible for the production of all blood cells and possess the dual ability to self-renew and differentiate into progenitor including precursors of B cells which complete their differentiation in the spleen. Given their importance, their physiology is tightly controlled by a plethora of signals that balance quiescence, proliferation, self-renewal and differentiation. The decreased repopulation and differentiation capacity of HSC during aging is believed to depend on several intrinsic and extrinsic factors, including aging-associated accumulation of ROS. At physiological level, ROS can regulate various cellular functions, including HSCs and lineage precursors proliferation, differentiation and mobilization. However, when intracellular ROS levels become excessive, they cause senescence or apoptosis, resulting in a premature exhaustion of HSCs and hematopoietic dysfunction. In this condition many signaling molecules are activated. Our laboratory has previously unveiled TP53INP1; indeed, TP53INP1- KO mice develop a chronic oxidative stress. The gene encoding TP53INP1 is expressed at basal level in all BM cell types, and strongly over-expressed when the BM upon aging. Analysis of BM cell compartments showed that the absence of TP53INP1 strongly impacts on B cell differentiation, which is surprisingly maintained in old KO BM while reduced in old WT. As shown by immunization assays, these B cells produce IgM and IgG showing that they are functional. Antioxidant treatment that scavenges ROS reverses the phenotype observed in old KO BM. Finally, we demonstrate that the B cell maintenance observed in KO old BM is due to an enhanced IL-7Rα/ pSTAT5 signaling pathways.