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 ß-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 ß-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 ß-cell function and/or growth in the adult. We have now generated pancreas-specific as well as ß-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 ß-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 ß-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)
- Assistant Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2006 – 2013)
- Adjunct Assistant Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2013– present)
- Ph.D., Developmental Biology, The Johns Hopkins University (2000)
- B.A., Biology, The Johns Hopkins University (1995)
- 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. Vol 62(3) . 2013 March:875-886.
- 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. Vol 4(3) . 2012 May:199-206.
- 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. Vol 365(1) . 2012 May:175-188.
- 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. Vol 359(1) . 2011 November:1-11.
- 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. Vol 286(17) . 2011 April:15352-15360.
- Das, P., May, C.L.. Expression analysis of the Islet-1 gene in the developing and adult gastrointestinal tract. Gene Expression Patterns. Vol 11(3-4) . 2011 March:244-254.
- 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. Vol 24(8) . 2010 June:1605-1614.
- May, C.L.. The role of Islet-1 in the endocrine pancreas Lessons from pancreas specific Islet-1 deficient mice. Islets. Vol 2(2) . 2010 March:121-123.
- 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. Vol 58(1-2) . 2009 September:2059-2069.
- White, P., May, C.L., Lamounier, R.N., Brestelli, J.E., Kaestner, K.H.. Defining pancreatic endocrine precursors and their descendants. Diabetes. Vol 57(3) . 2008 December:654-668.