24 research outputs found
Notch, un gĂšne clĂ© de lâĂ©quilibre entre prolifĂ©ration et diffĂ©renciation des cellules Ă©pithĂ©liales de lâintestin
In vivo imaging of mammary epithelial cell dynamics in response to lineage-biased Wnt/ÎČ-catenin activation
Notch Lineages and Activity in Intestinal Stem Cells Determined by a New Set of Knock-In Mice
The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells. In addition, a novel Notch reporter mouse, Hes1-EmGFPSAT, demonstrated exclusive Notch activity in crypt stem cells and absorptive progenitors. This roster of knock-in and reporter mice represents a valuable resource to functionally explore the Notch pathway in vivo in virtually all tissues
Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.
Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.Wellcome Trus
La sclérose en plaques (immunologie, traitements et perspectives d'avenir)
La sclĂ©rose en plaques (SEP) est une maladie auto-immune chronique du systĂšme nerveux central. La maladie se caractĂ©rise par la destruction de la gaine de myĂ©line perturbant la conduction de l influx nerveux. Les symptĂŽmes sont variĂ©s : troubles sensitifs, visuels, moteurs, fatigue, douleurs La maladie est caractĂ©risĂ©e par une succession de phases de poussĂ©es et de rĂ©missions. La prise en charge de la SEP est basĂ©e sur le traitement des poussĂ©es, le traitement de fond pour rĂ©duire la frĂ©quence des rechutes et la progression du handicap ; et le traitement symptomatique pour attĂ©nuer la gĂȘne quotidienne. La recherche progresse et vise Ă mieux comprendre les modalitĂ©s qui pourraient ĂȘtre mises en oeuvre pour protĂ©ger le systĂšme nerveux au cours de cette maladie. De nombreuses molĂ©cules sont en cours d essais cliniques dans le but d amĂ©liorer la prise en charge globale de la pathologie.LILLE2-BU SantĂ©-Recherche (593502101) / SudocSudocFranceF
Notch3 marks clonogenic mammary luminal progenitor cells in vivo
The identity of mammary stem and progenitor cells remains poorly
understood, mainly as a result of the lack of robust markers. The Notch
signaling pathway has been implicated in mammary gland development as
well as in tumorigenesis in this tissue. Elevated expression of the
Notch3 receptor has been correlated to the highly aggressive âtriple
negativeâ human breast cancer. However, the specific cells expressing
this Notch paralogue in the mammary gland remain unknown. Using a
conditionally inducible Notch3-CreERT2(SAT) transgenic mouse, we
genetically marked Notch3-expressing cells throughout mammary gland
development and followed their lineage in vivo. We demonstrate that
Notch3 is expressed in a highly clonogenic and transiently quiescent
luminal progenitor population that gives rise to a ductal lineage. These
cells are capable of surviving multiple successive pregnancies,
suggesting a capacity to self-renew. Our results also uncover a role for
the Notch3 receptor in restricting the proliferation and consequent
clonal expansion of these cells
Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells
International audienceColon tumours are hierarchically organized and contain multipotent self-renewing cells, called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1+ tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that shows reduced levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within intestinal tumours highlights the necessity of better understanding their hierarchy and behaviour, to identify the correct cellular targets for therapy
Luminal progenitors restrict their lineage potential during mammary gland development.
The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes
Alternatives au glyphosate en grandes cultures. Evaluation Ă©conomique: Evaluation Ă©conomique
Travail réalisé à la demande du Premier Ministre et des Ministres en charge de l'Agriculture et la Transition Ecologique et Solidaire, dans le cadre du plan de sortie du glyphosate.Alternatives au glyphosate en grandes cultures . Evaluation économiqu
Alternatives au glyphosate en grandes cultures. Evaluation économique. Résumé exécutif
Alternatives au glyphosate en grandes cultures. Evaluation économique. Résumé exécuti