test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works
       

Advanced Search
Home   
 
Browse   
Communities
& Collections
  
Issue Date   
Author   
Title   
Subject   
 
Sign on to:   
Receive email
updates
  
My Account
authorized users
  
Edit Profile   
 
Help   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/29668

Title: Regulation of Early T-cell Development and Commitment by HEB
Authors: Braunstein, Marsela
Advisor: Anderson, Michele K.
Department: Immunology
Keywords: T-cell development
hematopoiesis
E-proteins
HEB
thymus
TCRb-selection
Issue Date: 29-Aug-2011
Abstract: Early T-cell development is regulated by a complex interplay between transcription factors and developmental cues which ensure that functional T-cells are produced within the thymus. Early thymocytes integrate these signals in a step-wise fashion that progressively restricts their lineage potential as they transition through the early stages of T-cell development. Gene knockout studies have shown that the E-protein transcription factor HEB is required for normal thymocyte development. Furthermore, many additional key regulators such as Notch1 have been identified, but the connections among them and their specific roles in early T-cell development have not been well established. In this thesis, I set out to determine the specific roles of HEB at the beta-selection checkpoint and to establish connections between HEB and the key regulators within the gene regulatory network that orchestrates early T-cell development. To facilitate these studies, I generated a series of new mouse models including HEBAlt transgenic mice that express a short form of HEB called HEBAlt, which enabled me to answer specific questions and examine rare populations. First, my studies of HEB-/- mice allowed me to identify an early block in T-cell development, which was alleviated upon the addition of an HEBAlt transgene. Furthermore, I identified pTa and CD3e signalling as specific targets of HEBAlt during -selection. Second, my studies on HEB-/- mice revealed that they have a defect in T-cell commitment, with compromised Notch1 function and a tendency to become DN1-like cells. Moreover, the DN1-like cells could be induced to differentiate into thymic NK cells, revealing a role for HEB in the T/NK cell lineage decision. This study has revealed a new set of interactions among HEB, Notch1, and GATA3 that regulate the T-cell fate choice in developing thymocytes. Unexpectedly, my studies have also provided evidence for a role of HEBAlt in lymphomagenesis, highlighting the strict regulation of E-protein function that is necessary to ensure normal T-cell development.
URI: http://hdl.handle.net/1807/29668
Appears in Collections:Doctoral

Files in This Item:

File Description SizeFormat
Braunstein_Marsela_2011-06_PhD_thesis.pdf3.02 MBAdobe PDF
View/Open

This item is licensed under a Creative Commons License
Creative Commons

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

uoft