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.

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A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein͞ p300 to several classes of transcription factors. One of the p160 factors, p͞CIP͞AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREBbinding protein͞p300. In this manuscript, we report that p͞CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. Our data suggest that a short stature phenotype of p͞CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p͞CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals. N uclear receptors comprise a family of transcription factors that regulate gene expression in a ligand-dependent manner and include receptors for steroid hormones, such as estrogen and glucocorticoid, receptors for nonsteroidal ligands, such as thyroid hormone receptor and retinoic acid receptor, as well as receptors that bind diverse products of lipid metabolism (reviewed in refs. 1-5). A combination of genetic, biochemical, and functional data suggests that many factors, including the BRG (Swi͞Snf) complex (6), CREB-binding protein (CBP)͞p300, p160 factors, p͞CAF, and the TRAP͞DRIP͞ARC (7, 8) complex are likely to be critical regulators for at least subsets of nuclear receptor-regulated genes (9-15). However, by the simple criteria of ligand-dependent binding and the ability to synergize on cotransfection assays, numerous additional proteins have been suggested to exert coactivator roles (4, 5).Proteins of approximately 160 kDa molecular mass were among the first factors identified that interact with nuclear receptor in a highly ligand-dependent manner both in solution (16, 17) and on DNA (18) and could themselves associate with CBP (11, 12). Expression cloning and yeast two-hybrid screening approaches led to the identification of three related genes that encode these p160 factors, referred to as SRC-1͞NCoA-1, TIF2͞GRIP-1͞NCoA2, and p͞CIP͞AIB1͞ACTR͞RAC3͞ TRAM-1 (11,(19)(20)(21)(22)(23)(24)(25). These factors bind to nuclear receptors by interactions of LXXLL motif-containing helices within the interaction domain formed by conserved residues in helix3 and helix12 of the liganded receptor (5).Members of the p160 family of nuclear receptor coactivators contain a highly conserved N-terminal bHLH-PAS domain that is also present in members of the Per͞Arnt͞Sim family of transcription factors and mediates protein-protein interactions. Although several lines of evidence support the idea that p160 factors play important roles as...

Pituitary cell types arise in a temporally and spatially specific fashion, in response to combinatorial actions of transcription factors induced by transient signaling gradients. The critical transcriptional determinants of the two pituitary cell types that express the pro-opiomelanocortin (POMC) gene, the anterior lobe corticotropes, producing adrenocorticotropin, and the intermediate lobe melanotropes, producing melanocyte-stimulating hormone (MSH␣), have remained unknown. Here, we report that a member of the T-box gene family, Tbx19, which is expressed only in the rostral ventral diencephalon and pituitary gland, commencing on e11.5, marks pituitary cells that will subsequently express the POMC gene and is capable of altering progression of ventral cell types and inducing adrenocorticotropin in rostral tip cells. It is suggested that Tbx19, depending on the presence of synergizing transcription factors, can activate POMC gene expression and repress the ␣ glycoprotein subunit and thyroid-stimulating hormone ␤ promoters.

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