Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors

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 - 2010/3/16

Y1 - 2010/3/16

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

SN - 1534-5807

VL - 18

SP - 1022

EP - 1029

JO - Developmental Cell

JF - Developmental Cell

IS - 6

ER -