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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11262009-124114 |
| Date | 30 November 2009 |
| Creators | Wang, Sui |
| Contributors | Guoqiang Gu, Chin Chiang, Roland W. Stein, David Bader, Maureen A. Gannon |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11262009-124114/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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