We recently discovered novel, gut-restricted genes, Isx and Nkx6.3. Our research demonstrates that Isx is important for regulating metabolism and immunity in the intestine. In contrast, Nkx6.3 is pivotal for terminal differentiation of gastrin producing G cells of the stomach. Gastrin is a key component of acid production pathway in the stomach and plays an important role in cancer development and ulcer diseases of the esophagus, stomach, and intestine. We are in the process of elucidating how Isx and Nkx6.3 regulate other genes in these processes. Using the knowledge gained from these mouse models, we are also investigating how cells can differentiate or transdifferentiate by direct cellular reprogramming with transcription factors. Together, these studies represent novel approaches toward understanding fundamental aspects of gastrointestinal and hepatobiliary biology that are pertinent to regenerative medicine and cancer.
Dr. Michael Choi
Assistant Professor of Medicine, Harvard Medical School
Byeong-Moo Kim, Ph.D.
Shujie Chen, M.S.
Stem cell biology and regulation of hepatobiliary and gastrointestinal development. We recently identified a novel, intestine-restricted, homeodomain-containing transcription factor, Isx. Studies on the Isx-null ileum reveal dysregulated expression of SR-BI. We are in the process of elucidating how Isx regulates this and other related genes. We are also studying Isx and other transcriptional regulators that may be important for cell differentiation in the context of in vitro cellular reprogramming.
Functional analysis of the stomach- and hindbrain-restricted homeodomain transcription factor Nkx6.3 Homeodomain transcription factors are important for organogenesis and cell differentiation. The Nkx family illustrates these functions especially well, and the Nkx6 subfamily controls differentiation in central nervous system and pancreas. Nkx6.3, a recent addition to this subfamily, overlaps in expression with Nkx6.1 and Nkx6.2, but its main function is in the stomach. Nkx6.3 knockout mouse has severely reduced number of gastrin producing gastric G cells. They also have very low gastrin and acid levels in the stomach. We are in the process of investigating how Nkx6.3 cooperates with other gastric transcription factors to properly differentiate the stomach.
Kim BM, Choi MY. New Insights into the Role of Hedgehog Signaling in Gastrointestinal Development and Cancer. Gastroenterology. 2009 Aug;137(2):422-4. Epub 2009 Jun 27. PMID: 19563845
Hafler BP, Choi MY, Shivdasani RA, Rowitch D. Expression and function of Nkx6.3 in vertebrate hindbrain. Brain Res. 2008 Jul 30;1222C:42-50. Epub 2008 May 6.
Choi MY, Romer AI, Wang Y, Wu MP, Ito S, Leiter AB, Shivdasani RA. Requirement of the tissue-restricted homeodomain transcription factor Nkx6.3 in differentiation of gastrin-producing G cells in the stomach antrum. Mol Cell Biol. 2008 May;28(10):3208-18. Epub 2008 Mar 17.
Choi MY, Lauwers GY, Hur C, Willett CG, Chung DC. Microsatellite Instability is Frequently Observed in Rectal Cancer and Influenced by Neoadjuvant Chemoradiation. Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1584.
Choi MY, Romer AI, Hu M, Lepourcelet M, Mechoor A, Yesilaltay A, Krieger M, Gray PA, Shivdasani RA. A dynamic expression survey identifies transcription factors relevant in mouse digestive tract development. Development. 2006 Oct;133(20):4119-29. Epub 2006 Sep 13.