Ras mediated pathways antagonise Notch signalling, promoting B lymphogenesis in a T cell environment

Mason, Susan Margaret (2006) Ras mediated pathways antagonise Notch signalling, promoting B lymphogenesis in a T cell environment. MSc(R) thesis, University of Glasgow.

Abstract

Within the immune system an important lineage commitment decision faced by the haemopoietic progenitor cells (HPCs) is whether to adopt a T or B lymphocyte fate. Recent studies have indicated that Notch, a transmembrane receptor, plays a crucial role in inducing HPCs to adopt a T cell fate. Similarly transcription factors E2A, early B cell factor and Pax5 have been shown to be important in the generation of B lymphocytes from HPCs. Many of the upstream signalling pathways that regulate the expression and activation of these transcription factors remain largely undefined. To generate T cells from HPCs in vitro, we utilised foetal thymic organ culture (FTOC), high oxygen submersion FTOC techniques and the novel system OP9- DL1 a bone marrow stromal cell line expressing the Notch ligand Delta-like-1. HPCs, retrovirally infected with constitutively active Ras mutants, were cultured in each of the afore mentioned in vitro culture systems. Results indicate that constitutive activation of the Ras-mediated signalling pathways, by retrovirally infected cells with constitutively active RasV12, results in HPCs adopting a B cell fate within a T cell microenvironment. Furthermore, constitutive Ras-extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MARK) signalling may be key in promoting B cell fate within these systems as RasV12S35, which leads to a constitutive activation of Raf binding in the absence of PI3K binding, results in the adoption of a B cell fate. By contrast RasV12C40, which binds PI3K but not Raf, led to normal T cell fate adoption. Importantly, we have also shown in vivo that retrovirally infected HPCs adoptively transferred into neonatal recombination activating gene-1 deficient mice resulted in Ras/ERK- MAPK dependent B cell commitment within the thymus. These results suggest that constitutive Ras signals antagonise Notch-1 to promote B cell fate at the expense of T cell development.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Subjects: Q Science > QH Natural history > QH345 Biochemistry
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Michie, Dr. Alison
• Date of Award: 2006
• Depositing User: Mrs Monika Milewska-Fiertek
• Unique ID: glathesis:2006-30958
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 25 Oct 2018 15:06
• Last Modified: 21 May 2021 09:22
• URI: https://theses.gla.ac.uk/id/eprint/30958

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