Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors
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Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. / Schaffer, Ashleigh E; Freude, Karla Kristine; Nelson, Shelley B; Sander, Maike.
In: Developmental Cell, Vol. 18, No. 6, 2010, p. 1022-1029.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors
AU - Schaffer, Ashleigh E
AU - Freude, Karla Kristine
AU - Nelson, Shelley B
AU - Sander, Maike
N1 - Copyright 2010 Elsevier Inc. All rights reserved.
PY - 2010
Y1 - 2010
N2 - The molecular mechanisms that underlie cell lineage diversification of multipotent progenitors in the pancreas are virtually unknown. Here we show that the early fate choice of pancreatic progenitors between the endocrine and acinar cell lineage is restricted by cross-repressive interactions between the transcription factors Nkx6.1/Nkx6.2 (Nkx6) and Ptf1a. Using genetic loss- and gain-of-function approaches, we demonstrate that Nkx6 factors and Ptf1a are required and sufficient to repress the alternative lineage program and to specify progenitors toward an endocrine or acinar fate, respectively. The Nkx6/Ptf1a switch only operates during a critical competence window when progenitors are still multipotent and can be uncoupled from cell differentiation. Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development.
AB - The molecular mechanisms that underlie cell lineage diversification of multipotent progenitors in the pancreas are virtually unknown. Here we show that the early fate choice of pancreatic progenitors between the endocrine and acinar cell lineage is restricted by cross-repressive interactions between the transcription factors Nkx6.1/Nkx6.2 (Nkx6) and Ptf1a. Using genetic loss- and gain-of-function approaches, we demonstrate that Nkx6 factors and Ptf1a are required and sufficient to repress the alternative lineage program and to specify progenitors toward an endocrine or acinar fate, respectively. The Nkx6/Ptf1a switch only operates during a critical competence window when progenitors are still multipotent and can be uncoupled from cell differentiation. Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development.
KW - Animals
KW - Cell Differentiation
KW - Cell Lineage
KW - Epithelial Cells
KW - Gene Expression Regulation, Developmental
KW - Homeodomain Proteins
KW - Islets of Langerhans
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Multipotent Stem Cells
KW - Pancreas
KW - Pancreas, Exocrine
KW - Stem Cells
KW - Transcription Factors
U2 - 10.1016/j.devcel.2010.05.015
DO - 10.1016/j.devcel.2010.05.015
M3 - Journal article
C2 - 20627083
VL - 18
SP - 1022
EP - 1029
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 6
ER -
ID: 138433578