Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination.
While the biological roles of canonical Wnt/beta-catenin signaling in development and disease are well documented, understanding the molecular logic underlying the functionally distinct nuclear transcriptional programs mediating the diverse functions of beta-catenin remains a major challenge. Here, we report an unexpected strategy for beta-catenin-dependent regulation of cell-lineage determination based on interactions between beta-catenin and a specific homeodomain factor, Prop1, rather than Lef/Tcfs. beta-catenin acts as a binary switch to simultaneously activate expression of the critical lineage-determining transcription factor, Pit1, and to repress the gene encoding the lineage-inhibiting transcription factor, Hesx1, acting via TLE/Reptin/HDAC1 corepressor complexes. The strategy of functionally distinct actions of a homeodomain factor in response to Wnt signaling is suggested to be prototypic of a widely used mechanism for generating diverse cell types from pluripotent precursor cells in response to common signaling pathways during organogenesis.
Olson
Lorin E
LE
Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Tollkuhn
Jessica
J
Scafoglio
Claudio
C
Krones
Anna
A
Zhang
Jie
J
Ohgi
Kenneth A
KA
Wu
Wei
W
Taketo
Makoto M
MM
Kemler
Rolf
R
Grosschedl
Rudolf
R
Rose
Dave
D
Li
Xue
X
Rosenfeld
Michael G
MG