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Title page for ETD etd-11262009-124114


Type of Document Dissertation
Author Wang, Sui
Author's Email Address wangsui1015@gmail.com
URN etd-11262009-124114
Title The Myt1 and Ngn3 feed-forward expression loop drives pancreatic islet differentiation in the mouse
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Chin Chiang Committee Chair
David Bader Committee Member
Guoqiang Gu Committee Member
Maureen A. Gannon Committee Member
Roland W. Stein Committee Member
Keywords
  • Pancreatic development
  • Myt1
  • Ngn3
  • islet function
Date of Defense 2009-10-08
Availability unrestricted
Abstract
In humans, the proper growth and homeostasis of endocrine islets in the pancreas is of great medical importance, in that loss and dysfunction of islet cells result in Type 1 and Type 2 Diabetes Mellitus. One of the major goals of diabetic-related researches is to understand how islets are formed and matured during normal development, so as to aid functional islet production in vitro for transplantation-based diabetes therapies. It has been well established that a bHLH transcription factor Neurogenin3 (Neurog3 or Ngn3) plays essential roles in endocrine islet differentiation in mice. However, it remains unclear how Ngn3 levels are regulated in endocrine progenitors and how Ngn3 coordinates islet cell differentiation and function. Previously, a zinc-finger transcription factor Myt1 (Myelin transcription factor 1) was identified from a microarray-based study aiming for factors that are specifically enriched in Ngn3+ pancreatic endocrine progenitors. Here, we report that Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine differentiation. Specifically, loss of Myt1 partially compromises endocrine differentiation and islet function in the mouse pancreas, demonstrating that Myt1 plays a role in the generation of fully functional islet cells. Furthermore, although Myt1 expression largely depends on Ngn3 activity, Myt1 can enhance Ngn3 expression, suggesting that Myt1 contributes to endocrine commitment through Ngn3. To this end, reduced Ngn3 production at per cell level significantly impairs endocrine differentiation and endocrine/exocrine allocation. Finally, we discovered a previously unsuspected role of Ngn3 in islet cells. Sustained Ngn3 expression in hormone expressing endocrine islet cells is required for islet maturation and function. These studies not only provide important information regarding the regulation of endocrine differentiation, but also open up new directions to improve islet function under diabetic conditions.
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