title: The expression of dominant negative TCF7L2 in pancreatic beta cells during the embryonic stage causes impaired glucose homeostasis.
abstract: OBJECTIVE
  Disruption of TCF7L2 in mouse pancreatic β-cells has generated different outcomes in several investigations. Here we aim to clarify role of β-cell TCF7L2 and Wnt signaling using a functional-knockdown approach.
  
  
  METHODS
  Adenovirus-mediated dominant negative TCF7L2 (TCF7L2DN) expression was conducted in Ins-1 cells. The fusion gene in which TCF7L2DN expression is driven by P TRE3G was utilized to generate the transgenic mouse line TCF7L2DN Tet . The double transgenic line was created by mating TCF7L2DN Tet with Ins2-rtTA, designated as βTCFDN. β-cell specific TCF7L2DN expression was induced in βTCFDN by doxycycline feeding.
  
  
  RESULTS
  TCF7L2DN expression in Ins-1 cells reduced GSIS, cell proliferation and expression of a battery of genes including incretin receptors and β-cell transcription factors. Inducing TCF7L2DN expression in βTCFDN during adulthood or immediately after weaning generated no or very modest metabolic defect, while its expression during embryonic development by doxycycline feeding in pregnant mothers resulted in significant glucose intolerance associated with altered β-cell gene expression and reduced β-cell mass.
  
  
  CONCLUSIONS
  Our observations support a cell autonomous role for TCF7L2 in pancreatic β-cells suggested by most, though not all, investigations. βTCFDN is a novel model for further exploring the role of TCF7L2 in β-cell genesis and metabolic homeostasis.
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, M5S 2J7, Canada.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ip
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Fenghao
authors.initials: F
authors.lastname: Xu
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Zhuolun
authors.initials: Z
authors.lastname: Song
authors.affiliation: Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada ; McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Department of Physiology, University of Toronto, Medical Sciences Building, Room 7368, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Liang
authors.affiliation: Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
authors.affiliation: Department of Physiology, University of Toronto, Medical Sciences Building, Room 7368, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
authors.forename: Herbert
authors.initials: H
authors.lastname: Gaisano
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada ; McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada ; Department of Physiology, University of Toronto, Medical Sciences Building, Room 7368, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Nostro
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada ; Institute of Medical Science, University of Toronto, Toronto, ON, M5S 2J7, Canada ; McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
keywords: GLP-1; GSIS; Incretin receptors; Pancreatic β-cells; TCF7L2; TCF7L2DN; Wnt
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