Reciprocal Interactions of Pit1 and GATA2 Mediate Signaling Gradient–Induced Determination of Pituitary Cell Types

• Published in: Cell Vol. 97; no. 5; pp. 587 - 598
• Main Authors: Dasen, Jeremy S, O’Connell, Shawn M, Flynn, Sarah E, Treier, Mathias, Gleiberman, Anatoli S, Szeto, Daniel P, Hooshmand, Farideh, Aggarwal, Aneel K, Rosenfeld, Michael G
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.1999
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; COS Cells; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; GATA2 Transcription Factor; Genes, Reporter; Homeodomain Proteins - metabolism; Mice; Mice, Transgenic; Molecular Sequence Data; Mutagenesis, Site-Directed; Pituitary Gland - cytology; Pituitary Gland - metabolism; Point Mutation; Promoter Regions, Genetic; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Signal Transduction; Thyrotropin - genetics; Transcription Factor Pit-1; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Zinc Fingers
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80770-9

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.