Transcriptional regulation of pancreatic and gastrointestinal development and function using mouse models.
Key words: Diabetes, beta cell, alpha cell, pancreas development, gastrointestinal differentiation, transcription, Islet-1, LIM-HD proteins.
Description of Research:
Transcriptional control of pancreatic development and pancreatic β-cell function and growth by Isl-1
We are investigating the role of Isl-1 in the development of the pancreas as well as in maintaining proper pancreatic β-cell function. Isl-1 expression is detected in the developing pancreas and is later restricted to all pancreatic endocrine cells in the adult islets. This expression analysis, along with the fact that Isl-1 mutations have been identified in individuals with type II diabetes, suggests that Isl-1 may be involved in endocrine cell differentiation as well as in maintaining pancreatic β-cell function and/or growth in the adult. We have now generated pancreas-specific as well as β-cell specific deletions of Isl-1 in the mouse. These mouse models will be used to analyze the phenotypic consequences of these mutations for pancreas development, function and growth. We are also interesting in identifying the cofactor(s) (ie Ldb1) that are required to mediate the actions of Isl-1 in the developing endocrine and mature β-cell.
Transcriptional control of enteroendocrine cell differentiation by Isl-1:
Enteroendocrine cells in the gastrointestinal epithelium regulate many aspects of gastrointestinal activity including glucose metabolism, delivery of bile and pancreatic secretions, and gut epithelial renewal. Isl-1 expression is detected in subsets of enteroendocrine cells in the gastric epithelium of the rat. To better understand the role of Isl-1 during the development of gastric epithelium, we are planning to characterize the expression pattern of Isl-1 in mice as well as generate various stomach/endoderm specific deletions of Isl-1 mouse models.
Investigate the role of Isl-1 and Arx during pancreas development and function using mouse models.
Identify direct downstream targets of Isl-1 in the developing and mature β-cell using ChIP-Seq technology and microarray analysis.
Investigate the role of Ldb1 during pancreas development and function using mouse models.
Characterize Isl-1 expression in the developing gastrointestinal tract.
Investigation of Isl-1 function during gastrointestinal development using mouse models.
Christine Reid, Ph.D. (Postdoctoral Fellow)
Natalie Terry, M.D. Ph.D (Pediatric GI Fellow)
Crystal Wilcox (CAMB Graduate Student)
Benjamin Ediger (CAMB Graduate Student)
Mark Ferreira (CAMB Combined degree: M.D/Ph.D Student)
Erik Walp (Research Technician/Lab Manager)
Hunter, C., Dixit, S., Cohen, T., Ediger, B., Wilcox, C., Ferreira, M., Westphal, H., Stein, R., May, C.L.: Islet alpha, beta, and delta cell development is controlled by the Ldb1 coregulator, acting primarily with the Isl1 transcription factor. Diabetes 62(3): 875-886, March 2013.
Liu, J., Walp, E.R., May, C.L.: Elevation of transcription factor Islet-1 levels in vivo increases beta cell function but not beta cell mass Islets 4(3): 199-206, May 2012.
Du, A., McCracken, K., Walp, E., Terry, N.A., Klein, T.J., Han, A., Wells, J., May., C.L.: Arx is required for normal enteroendocrine cell development in mice and humans Developmental Biology 365(1): 175-188, May 2012.
Mastracci, T.L., Wilcox, C, Arnes, L., Panea, C., Golden, J.A., *May, C.L., *Sussel, L. : Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression. Developmental Biology 359(1): 1-11, November 2011 Notes: *Co-corresponding authors.
Liu, J., Hunter, C., Du, A., Ediger, B., Walp, E., Murray, J., Stein, R., May, C.L. : Islet-1 regulates Arx transcription during pancreatic islet alpha-cell development. Journal of Biological Chemistry 286(17): 15352-15360, April 2011.
Das, P., May, C.L. : Expression analysis of the Islet-1 gene in the developing and adult gastrointestinal tract
Gene Expression Patterns 11(3-4): 244-254, March 2011.
Hancock, A.S., Du, A., Liu, J., Miller, M., May, C.L. : Glucagon deficiency reduces hepatic glucose production and improve glucose tolerance in adult mice. Molecular Endocrinology 24(8): 1605-1614, June 2010.
May, C.L.: The role of Islet-1 in the endocrine pancreas Lessons from pancreas specific Islet-1 deficient mice Islets 2(2): 121-123, March 2010.
Du. A., Hunter, C.S., Murray, J., Noble, D., Cai, C.-L., Evans, S.M., Stein, R., May, C.L.: Islet-1 is required for the maturation, proliferation and survival of the endocrine pancreas. Diabetes 58(1-2): 2059-2069, September 2009.
White, P., May, C.L., Lamounier, R.N., Brestelli, J.E., Kaestner, K.H. : Defining pancreatic endocrine precursors and their descendants. Diabetes 57(3): 654-668, December 2008.
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Last updated: 10/03/2013
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