The goal of the proposed research is to define the developmental program for the pancreatic acinus. A mature, functional acinus is composed of acinar cells, which surround a specialized form of intercalated duct (the centroacinar cells), and the proximal connecting duct (the intercalated duct). We propose that these three cell-types arise as a single developmental unit from a common progenitor cell-type, the terminal tubule cell of the embryonic pancreas. This model is based on the use of new markers that reveal a developmental intermediate reminiscent of the mature acinus, with gene expression boundaries that suggest discrete developmental compartments with specific functions. To examine this model we will define the roles of two key transcriptional regulators, Ptf1a and Nr5a2, through biochemical and genetic analyses. Ptf1a is expressed in two temporal waves during pancreatic organogenesis: at the onset of pancreatic budding and then at super-induced levels during the secondary transition in multipotent precursor cells and nascent acinar cells, where it appears to control differentiation. We will determine the developmental signals and transcription factors that reactivate the expression of the Ptf1a gene for the beginning of acinar development. We have recently shown that Nr5a2 is required during pancreatic development specifically for the formation of acini and is a direct target of PTF1a.
Aim 1 will determine the regulatory mechanisms whereby the nuclear receptor NR5A2 controls the early stage of acinar development.
Aim 2 will define the regulatory properties of the transcriptional enhancer that reactivates Ptf1a expression in newly forming acinar cells by identifying DNA-binding transcription factors that mediate the activity of the enhancer and determine which of these factors are required for the regulation of Ptf1a expression during embryogenesis and for normal acinar development.
Aim 3 will determine the manner in which Wnt and Notch developmental signal are integrated into transcriptional activation of the Ptf1a gene during embryonic development.

Public Health Relevance

Pancreatitis and pancreatic cancer are common diseases of the pancreas. By understanding the control of normal development of the exocrine pancreas we hope to contribute to therapies that may help a pancreas badly damaged by pancreatitis to regenerate, or to identify ways to stop the growth of cancer cells derived from the exocrine pancreas without damaging other cells of the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061220-10
Application #
8447545
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
2001-09-30
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$322,966
Indirect Cost
$117,255
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hale, Michael A; Swift, Galvin H; Hoang, Chinh Q et al. (2014) The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis. Development 141:3123-33
Afelik, Solomon; Qu, Xiaoling; Hasrouni, Edy et al. (2012) Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells. Development 139:1744-53
Direnzo, Daniel; Hess, David A; Damsz, Barbara et al. (2012) Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. Gastroenterology 143:469-80
Johnson, Jane E; Macdonald, Raymond J (2011) Notch-independent functions of CSL. Curr Top Dev Biol 97:55-74
Holmstrom, Sam R; Deering, Tye; Swift, Galvin H et al. (2011) LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function. Genes Dev 25:1674-9
Masui, Toshihiko; Swift, Galvin H; Deering, Tye et al. (2010) Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells. Gastroenterology 139:270-80
Henke, R Michael; Savage, Trisha K; Meredith, David M et al. (2009) Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development 136:2945-54
Masui, Toshihiko; Swift, Galvin H; Hale, Michael A et al. (2008) Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. Mol Cell Biol 28:5458-68
Hori, Kei; Cholewa-Waclaw, Justyna; Nakada, Yuji et al. (2008) A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling. Genes Dev 22:166-78
Masui, Toshihiko; Long, Qiaoming; Beres, Thomas M et al. (2007) Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev 21:2629-43

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