Temporal regulation of a paired-like homeodomain repressor/TLE corepressorcomplex and a related activator is required for pituitary organogenesis

Understanding the functional significance of the coordinate expression of s pecific corepressors and DNA-binding transcription factors remains a critic al question in mammalian development. During the development of the pituita ry gland, two highly related paired-like homeodomain factors, a repressor, Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlappin g temporal patterns. Here we show that while the repressive actions of Hesx 1/Rpx may be required for initial pituitary organ commitment, progression b eyond the appearance of the first pituitary (POMC) lineage requires both lo ss of Hesx1 expression and the actions of Prop-1. Although Hesx1 recruits b oth the Groucho-related corepressor TLE1 and the N-CoR/Sin3/HDAC complex on distinct domains, the repressor functions of Hesx1 in vivo prove to requir e the specific recruitment of TLE1, which exhibits a spatial and temporal p attern of coexpression during pituitary organogenesis. Furthermore, Hesx1-m ediated repression coordinates a negative feedback loop with FGF8/FGF10 sig naling in the ventral diencephalon, required to prevent induction of multip le pituitary glands from oral ectoderm. Our data suggest that the opposing actions of two structurally-related DNA-binding paired-like homeodomain tra nscription factors, binding to similar cognate elements, coordinate pituita ry organogenesis by reciprocally repressing and activating target genes in a temporally specific fashion, on the basis of the actions of a critical, c oexpressed TLE corepressor.