Delineation of the cellular pathway and molecular mechanisms of Notch1-Mediated early T Lineage development / Anthony Wei Shine Chi.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Chi, Anthony Wei Shine.

Contributor:

Bhandoola, Avinash, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Allergy and Immunology.

Academic Dissertations as Topic.

Medical Subjects:

Allergy and Immunology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Physical Description:

vi, 117 pages : color illustrations ; 29 cm

Production:

[Philadelphia], 2011.

Summary:

T lineage development takes place outside the bone marrow (BM) in a dedicated organ, the thymus. Containing no long-termed self-renewing progenitors, the thymus requires periodic importations of progenitors from the BM. Within the thymus, Notch1 ligands, Delta-like 4, induce Notch1 signaling in incoming progenitors and initiate T cell differentiation programming. This thesis work aims to further elucidate mechanisms downstream of Notch1 during early T lineage development. In the first chapter, I describe a small subset of myeloid progenitors that still retain T lymphoid developmental potential. Yet these progenitors are unlike to contribute to the thymopoiesis under normal physiological conditions, as they lack proper chemokine receptors for optimal thymic homing. In the second chapter, I demonstrate TCF1 is a Notch1 target gene and IL7Ralpha is a TCF1 target gene. IL7R signaling has been shown to provide the trophic signals during T lineage development. This, in addition to the fact that TCF1 regulates key T lineage genes, such as TCRalpha and CD3epsilon, suggests TCF1 may function as a critical mediator that couples the specification process in T lineage differentiation with the survival requirement. Lastly, Notch1 is previously shown to be able to dimerize. In the third chapter, I show that, while dispensable to impose the T cell fate on multipotent progenitors, Notch1 dimerization is required to differentiate DN3 thymocytes to the CD4 +CD8+ DP stage in part through activation of cMyc expression. Given that Notch1 regulates key target genes via dimerization and developmental stage-specific blocks ensue when dimerization is prevented, this finding is of potential clinical interest, as it may be possible to develop a new class of Notch inhibitors that selectively block Notch1 dimerization-dependent outcomes, such as leukemogenesis.

Notes:

Adviser: Avinash Bhandoola.

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2011.

Includes bibliographical references.