Deficiencies in the homeobox transcription factors LHX4 and PROP1 cause pituitary

The pituitary gland is known as the master gland because it controls the release of hormones that affect diverse processes including growth, metabolism and fertility. Many of the genes necessary for normal development and function of the specialized hormone producing cells of the anterior pituitary lobe have been identified (Dasen and Rosenfeld, 2001; WatkinsChow and Camper, 1998) The key genes fall into several groups: transcription factors, secreted signaling molecules and receptors. Each transcription factor shown to be important in mouse pituitary development is also a cause of congenital pituitary hormone deficiency in humans, a common condition occurring with a frequency of 1 in 4000 births (Procter et al., 1998; Vimpani et al., 1977). The excellent correspondence of mouse and human pituitary phenotypes suggests that mouse studies will be ideal to characterize the undefined genetic interactions between these transcription factors. The pituitary gland develops from an invagination of oral ectoderm known as Rathke’s pouch (Burrows et al., 1999; Watkins-Chow and Camper, 1998). The pouch is in contact with the ventral diencephalon, infundibulum or prospective posterior lobe, and surrounding mesenchyme. Each of these adjacent tissues secrete signaling molecules that establish spatial orientation and identity of the pouch. Experimental evidence supports the involvement of BMP4, FGF8, FGF10, SHH, BMP2, WNT4, and chordin (Ericson et al., 1998; Takuma et al., 1998; Treier et al., 1998). FGF8 and FGF10 produced by the infundibulum, and BMP2 from the ventral mesenchyme, constitute opposing signals that activate regionspecific expression of the lim homeodomain transcription factors LHX3 and ISL1 in the dorsal and ventral regions of the pouch respectively (Ericson et al., 1998). The stereotypic pattern of activation of these transcription factors is critical for determination of the corticotropes (cells that synthesize adrenocorticotropic hormone or ACTH) and the cells that produce αGSU, the common subunit of thyrotropin (TSH) and the gonadotropins (luteinizing hormone, LH, and follicle stimulating hormone, FSH). Very few additional links have been made between signaling molecules, transcription factor activation, and the specification of hormone producing cells. The roles of transcription factors in cell specification have been illuminated by both molecular and genetic studies (Dasen and Rosenfeld, 2001; Watkins-Chow and Camper, 1998). Related transcription factors have overlapping functions in early development. The bicoid type transcription factors Pitx1 and Pitx2 are expressed throughout the oral ectoderm at the earliest stages of pituitary specification (Suh et al., 2002). Pitx2 is required for expansion of the pouch and has a later role in specification of gonadotropes and expansion of the Pit1 lineage: thyrotropes, somatotropes and lactotropes (Suh et al., 2002). Pitx1 has a minor role in expansion of the individual specialized cells, affecting only the relative proportions of each cell type (Szeto et al., 1999). Deficiency in both Pitx1 and Pitx2 causes an earlier arrest in development than caused by lesions in either gene alone (Suh et al., 2002). 4229 Development 129, 4229-4239 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV3661