Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.

The 'paired'-like homeodomain transcription factor Prop1 is essential for the expansion of the pituitary primordia and for the differentiation and/or function of the hormone-producing cells of the anterior pituitary gland. Prop1 expression is normally extinguished before transcription of most differentiation markers is initiated. We report that constitutive expression of Prop1 interferes with anterior pituitary cell differentiation and increases the susceptibility for pituitary tumors. The terminal differentiation of pituitary gonadotropes is delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurs normally, but thyrotrope function is impaired resulting in mild hypothyroidism. Aged mice exhibit defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke's cleft cysts and tumors. Thus, silencing Prop1 is important for normal pituitary development and function. These data suggest that gain-of-function mutations in PROP1 could contribute to the most common human pituitary endocrinopathies and tumors.

Thyroid hormone is essential for pituitary somatotropes and lactotropes.

Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types.

How many homeobox genes does it take to make a pituitary gland?

The secrets of anterior pituitary development and cell lineage determination have been revealed mostly by genetic analyses. The requirement for three homeobox genes, Lbx3, Lbx4 and Titf1, during early organogenesis was proven by gene targeting. Spontaneous mouse mutations revealed two additional homeobox genes, Pit1 and Prop1, that are critical for specialization and proliferation of subsets of the five differentiated cell types. Analysis of patients with pituitary insufficiency has demonstrated the importance of these two genes in human pituitary function. Recently, several other homeobox genes have been identified and implicated in pituitary organogenesis. Genetic manipulations of these genes will undoubtedly add to the emerging genetic hierarchy regulating the ontogeny of this major hormone-producing gland.

Construction of a 3-Mb contig and partial transcript map of the central region of mouse chromosome 11.

We report the establishment of a high-resolution genetic map, a physical map, and a partial transcript map of the Ames dwarf critical region on mouse chromosome 11. A contig of 24 YACs and 13 P1 clones has been assembled and spans approximately 3 Mb from Flt4 to Tcf7. A library of approximately 1000 putative transcript clones from the region was prepared using exon amplification and pituitary cDNA selection. Ten novel transcripts were partially characterized, including a member of the olfactory receptor family, an alpha-tubulin-related sequence, and a novel member of the cdc2/CDC28-like kinase family, Clk4. The location of Prop1, the gene responsible for Ames dwarfism, has been localized within the contig. This contig spans a region of mouse chromosome 11 that exhibits linkage conservation with human chromosome 5q23-q35. The strength of the genetic map and genomic resources for this region suggest that comparative DNA sequencing of this region could reveal the genes responsible for other mouse mutants and human genetic diseases.

Genetic mapping of 21 genes on mouse chromosome 11 reveals disruptions in linkage conservation with human chromosome 5.

We report a high-resolution genetic map of 21 genes on the central region of mouse Chr 11. These genes were mapped by segregation analysis of more than 1650 meioses from three interspecific backcrosses. The order of these genes in mouse was compared to the previously established gene order in human. Eighteen of the 21 genes map to human Chr 5, and 2 of the genes define a proximal border for the region of homology between mouse Chr 11 and human Chr 17. Our results indicate a minimum of four rearrangements within the 10-cM region of synteny homology between mouse Chr 11 and human Chr 5. In addition, the linkage conservation is disrupted by groups of genes that map to mouse Chrs 13 and 18. These data demonstrate that large regions of conserved linkage can contain numerous chromosomal microrearrangements that have occurred since the divergence of mouse and human ancestors. Comparison of the mouse and human maps with data for other species provides an emerging picture of mammalian chromosome evolution.