Candidate genes for panhypopituitarism identified by gene expression profiling

Abstract

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease.

Identification and Analysis of Two Novel Sites of Rat GnRH Receptor Gene Promoter Activity: The Pineal Gland and Retina

“…As expected, Otx2 mRNA was detected in both the retina and pineal. Interestingly, and as expected from recent data of the literature (see Introduction and Mortensen et al [41]), Otx2 mRNA was also expressed in the pituitary.…”

Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells

“…FACS-sorted E-cadherinand E-cadherin + cells were defined as hypothalamus and oral ectoderm cells, respectively. (B) Quantitative RT-PCR of OTX2 in FACS-sorted hypothalamus and oral ectoderm (day [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. OTX2 expression was higher in hypothalamus than in oral ectoderm.…”

“…OTX2 protein binds to the promoters of HESX1 and POU1F1, which are expressed in oral ectoderm and required for pituitary development, and directly upregulates their expression (11,12,14), suggesting the role of OTX2 expressed in the oral ectoderm. On the other hand, it has been shown that not oral ectoderm-specific but hypothalamus-specific Otx2-deficient mice exhibited impaired anterior pituitary development, suggesting that the OTX2 expressed in the hypothalamus plays an important role in pituitary development (15,16); however, the precise underlying mechanisms, especially in humans, remain unclear.…”

Pituitary Gland Development and Disease

“…Otx1 -/- mutants have an even milder phenotype, resulting in a transient delay in growth and puberty 92 , supporting the idea that both Otx1 and Otx2 have roles in pituitary development, with Otx2 being the most critical for normal organ morphology and function. Otx2 is prominently expressed in the neural ectoderm, which produces FGF and stimulates the growth of Rathke’s pouch 79 . Otx2 expression in Rathke’s pouch is very low and transient, and little or no expression is apparent when Pou1f1 transcription is initiated.…”