Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types.
The mechanisms by which transient gradients of signaling molecules lead to emergence of specific cell types remain a central question in mammalian organogenesis. Here, we demonstrate that the appearance of four ventral pituitary cell types is mediated via the reciprocal interactions of two transcription factors, Pit1 and GATA2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA binding-independent function of Pit1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to generate distinct cell phenotypes.
Dasen
J S
JS
Howard Hughes Medical Institute, Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla 92093-0648, USA.
O'Connell
S M
SM
Flynn
S E
SE
Treier
M
M
Gleiberman
A S
AS
Szeto
D P
DP
Hooshmand
F
F
Aggarwal
A K
AK
Rosenfeld
M G
MG
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050989:GATA2 Transcription Factor; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010902:Pituitary Gland / Q000166:cytology* / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013972:Thyrotropin / Q000235:genetics; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; D013972:Thyrotropin; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494712:Gata2 protein, mouse; C494713:Gata2 protein, rat; C494185:Pou1f1 protein, mouse; C494186:Pou1f1 protein, rat