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 org anogenesis. Here, we demonstrate that the appearance of four ventral pituit ary cell types is mediated via the reciprocal interactions of two transcrip tion factors, Pit1 and GATA2, which are epistatic to the remainder of the c ell type-specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DN A binding-independent function of Pit1, suppressing the ventral GATA2-depen dent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but no t thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to generat e distinct cell phenotypes.