Department of Human Genetics, Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA.
Physiol Genomics. 2011 Oct 6;43(19):1105-16. doi: 10.1152/physiolgenomics.00080.2011. Epub 2011 Aug 9.
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.
转录因子 PROP1 和 PIT1（POU1F1）的突变导致小鼠和人类的垂体激素缺乏和垂体功能减退。发育中的 Prop1 突变体垂体的畸形很容易将其与 Pit1 突变体和正常小鼠的垂体区分开来。这一特征和其他特征表明，Prop1 除了控制 Pit1 之外，还控制着对垂体细胞迁移、存活和分化很重要的基因的表达。为了鉴定这些过程中涉及的基因，我们使用基因表达的微阵列分析来比较新生 Prop1 和 Pit1 突变体和正常同窝仔鼠的垂体 RNA。每个突变体与其正常同窝仔鼠以及 Prop1 和 Pit1 突变体之间的基因表达都存在显著差异。Otx2 是人类和小鼠中正常眼睛和垂体发育的关键基因，其表达在 Prop1 突变体垂体中特异性升高。我们报告了 Otx2 在正常小鼠和 Prop1 突变体中的时空调节，结果表明 Otx2 可以通过影响腹侧神经胚层的信号传递和 Rathke 囊的基因表达调节来影响垂体发育。Otx2 表达受 Prop1 缺乏影响的发现为我们的假设提供了支持，即鉴定突变体中的分子差异将有助于理解控制垂体发生的分子机制，并导致人类垂体疾病。
