A new step understood in the cascade of tissue-specific regulators orchestrating pituitary lineage determination: the Prophet of Pit-1 (Prop-1).

An early step in generating specific cell types in embryos involves the commitment of multipotent stem cells to specific lineages. The anterior pituitary gland, with its five cell types originating from a common precursor, provides an instructive model to approach the mechanisms that control mammalian organ development and cell differentiation. Using the well-known model of the Ames dwarf mouse, which has a hypoplastic pituitary due to a dramatic reduction of somatotroph, lactotroph and thyrotroph cells, M Rosenfeld’s group has been able to clone the defective gene responsible for Ames’ dwarfism and has therefore clarified a new step in the cascade of tissue-specific regulators orchestrating the development of the anterior pituitary. They identified a novel pituitary paired-like homeodomain factor which seemed to be an important prerequisite for the expression of the transcription factor Pit-1. They named it Prophet of Pit-1 (Prop-1) (1). Pit-1 had been discovered in another dwarf mouse, the Snell and Jackson mouse. These animals also lack growth hormone, prolactin and thyrotrophin (TSH) and it has been shown that this results from a mutation in the Pit-1 gene resulting in a non-functional Pit-1 protein (2). Now the work of Rosenfeld and colleagues (1) indicates that a mutation of Prop-1 induces a specific defect in the determination of the Pit-1 lineages in the Ames dwarf mouse. The development of the pituitary depends on many factors. In short, Rathke’s pouch, the primordium of the anterior pituitary, appears as an invagination of an ectodermal layer of cells that contacts the neuroectoderm of the primordium of the ventral hypothalamus at embryonic day (E) 8.5 in the mouse. Before the formation of Rathke’s pouch, some genes have been identified allowing certain cell compartments to develop into an anterior pituitary and expressing three homeodomain factors, Pax6, Rpx (Rathke’s pouch homeobox) and Six3 (3). Concurrently to the invagination of the Rathke’s pouch, the expression of two homeodomain factors, the LIM homeobox gene Lhx3 (also known as P-Lim and mLim-3) and an OTX-related factor (Ptx1/ P-OTX) are seen. Lhx3 is required for the commitment of gonadotrophs, thyrotrophs, somatotrophs and lactotrophs. The further differentiation of the Lhx3/Ptx1 cells is dependent upon the appearance of two transcription factors: Pit-1 and the orphan nuclear receptor SF-1 (steroidogenic-factor 1). They are both detected at E13.5 in the anterior pituitary gland. In the Ames dwarf mouse (df), the defective gene has been mapped to a locus on mouse chromosome 11, distinct from the Pit-1 gene located on chromosome 6. Contrary to the normal expression of the Pit-1 mutated gene in Snell and Jackson (dw) animals, in the case of the Ames dwarf mouse in situ hybridization and immunohistochemical studies have failed to detect Pit-1, thus strongly indicating that the Ames dwarf (df) defective gene is required for initial activation of the Pit-1 gene (4). This gene can now be identified with a completely new technique (5), highest homology with homeodomain factors being most closely related to Aristaless and Gooseberry. Because the df mutation induces a failure of initial determination of Pit-1 lineages, the gene encoding the new homeodomain factor was termed Prophet of Pit-1 (Prop-1). The df allele encodes a Ser-Pro mutation of the alpha 1 helix of the Prop-1 homeodomain. This mutation is responsible for the functional impairment of Prop-1 as Prop-1 mutated protein was significantly impaired in DNA binding (eightfold lower affinity on a high affinity site, PRDQ9). The mutation induces a great reduction in transcriptional activation. Prop-1 ontogeny of expression is of great interest: its expression is restricted to the pituitary and appears by E10-E10.5, preceding that of Pit-1 by three days. Its peak expression is at E12, decreasing after E14.5. The df/df pituitary development is normal before E12 when even in normal animals Prop-1 is weakly expressed. The dysmorphogenesis appears by E13 and the recently divided cells fail to accumulate in the caudomedial region where Pit-1 is normally expressed. The appearance of dysmorphogenesis follows immediately the peak of Prop-1, which is again due to the role of Prop-1 in the df defect. Therefore, df defect associates the failure of determination of Pit-1 lineages, the lack of Pit-1 gene activation, the failure of progression to mature cells, and a prolonged expression of markers, such as Brn-4 and Rpx, characteristic of the non-committed cells. Interactions between homeodomain factors during pituitary ontogenesis has been shown previously. For example, P-Lim synergize with Pit-1 in transcriptional activation of genes encoding terminal differentiation markers. Because of the coexpresssion of Rpx (Rathke’s pouch homeobox) and Prop-1 from E10 to European Journal of Endocrinology (1997) 137 616–617 ISSN 0804-4643