Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development.
Understanding the cell type-specific molecular mechanisms by which distinct signaling pathways combinatorially control proliferation during organogenesis is a central issue in development and disease. Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes. Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1. Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction. The molecular strategy underlying interactions between the Wnt and growth factor-dependent signaling pathways in cardiac outflow tract and pituitary proliferation is likely to be prototypic of cell-specific proliferation strategies in other tissues.
Kioussi
Chrissa
C
Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, CMM-West, Room 345, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Briata
Paola
P
Baek
Sung Hee
SH
Rose
David W
DW
Hamblet
Natasha S
NS
Herman
Thomas
T
Ohgi
Kenneth A
KA
Lin
Chijen
C
Gleiberman
Anatoli
A
Wang
Jianbo
J
Brault
Veronique
V
Ruiz-Lozano
Pilar
P
Nguyen
H D
HD
Kemler
Rolf
R
Glass
Christopher K
CK
Wynshaw-Boris
Anthony
A
Rosenfeld
Michael G
MG
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D000072261:Dishevelled Proteins; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009687:Nuclear Proteins; D038081:Organogenesis / Q000235:genetics*; D010750:Phosphoproteins; D010902:Pituitary Gland / Q000196:embryology; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2
D048868:Adaptor Proteins, Signal Transducing; D056742:Cyclin D2; D016213:Cyclins; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2; C495267:CTNNB1 protein, mouse; C486196:Ccnd2 protein, mouse