Control of pituitary cell plasticity through regulated mRNA translation

总结 垂体前叶作为生物体的内分泌核心，调节激素合成， 分泌以适应不断变化的代谢和生殖需求。垂体源性 激素，由于遗传原因，头部受伤，营养不足或营养过剩，或由于垂体癌 治疗导致严重的发病率。很久以前就知道脑垂体前叶的细胞 命运的显著可塑性表明存在干细胞样细胞群。然而，无论干 细胞确实有助于细胞的可塑性和垂体的恢复，以及控制垂体功能的潜在机制。 垂体细胞可塑性对垂体损伤、激素需求变化或肿瘤进展的反应， 尚未成立。mRNA翻译控制蛋白Musashi已被证明在转录过程中起着关键作用。 在许多组织类型中介导生理和病理干细胞功能。武藏介干 通过抑制编码细胞周期所需蛋白质的靶mRNA的翻译实现细胞自我更新 抑制和细胞分化。我们的数据表明，武藏广泛表达于成人前额叶， 在非干细胞群体中的垂体，以及在垂体干细胞中。 本申请的总体目标是评估一般而言受调节的mRNA翻译的作用，以及mRNA翻译的调节。 具体而言，Musashi蛋白介导垂体细胞命运的适应性变化。核心假设 武藏控制着垂体干/祖细胞的分化和可塑性 成年人脑垂体中的激素分泌细胞。具体而言，目标1的研究将在体内使用 小鼠模型和细胞培养方法来测试武藏调节细胞可塑性的假设， 组织再生以及发育垂体干/祖细胞功能。目标2的研究将使用 无偏见的基于多聚体的RNA测序方法来测试武藏具有性别特异性的假设， mRNA靶点和RNA靶向机制，控制干/祖细胞中的细胞命运决定， 成体细胞群的适应性反应。 这项研究的结果将充分告知该领域关于武藏活动和mRNA翻译的作用 垂体细胞可塑性和干/祖细胞功能的控制。此外，这些研究建议 涉及内分泌和代谢疾病的治疗方法，特别是由垂体 缺陷由于激素替代策略不能完全模拟生理脉冲分泌机制， 促进缺失的内分泌细胞谱系再生的研究将是一项重要的临床研究， 改进.这将积极影响性别适当的治疗模式，联合垂体 激素缺乏、代谢性疾病与脑损伤后垂体组织修复

SUMMARY The anterior pituitary functions as the endocrine core of the organism, regulating hormonal synthesis and secretion to effect adaption to changing metabolic and reproductive needs. Deficiencies of pituitary-derived hormones, due to genetic causes, head injury, under or over-nutrition, or as a consequence of pituitary cancer treatment cause severe morbidity. The cells of the anterior pituitary have been long known to possess remarkable plasticity of fate suggesting the presence of stem cell-like cell populations. However, whether stem cells do indeed contribute to cell plasticity and pituitary recovery and the underlying mechanisms that control pituitary cell plasticity in response to pituitary injury, changing hormonal demands or tumor progression have not been established. The mRNA translation control protein, Musashi, has been shown to plays a critical role in mediating physiological and pathological stem cell function in many tissue types. Musashi mediates stem cell self renewal by repressing translation of target mRNAs that encode proteins required for cell cycle inhibition and cell differentiation. Our data indicate that Musashi is broadly expressed in the adult anterior pituitary in non-stem cell populations, as well as in pituitary stem cells. The overall objective of this application is to assess the role of regulated mRNA translation in general, and the Musashi protein specifically, in mediating adaptive changes of cell fate in the pituitary. The central hypothesis is that Musashi controls both pituitary stem/progenitor cell differentiation and also plasticity of hormone producing cells in the adult pituitary. Specifically, studies for Aim 1 will use both in vivo mouse models and cell culture approaches to test the hypothesis that Musashi regulates cell plasticity during tissue regeneration as well as developmental pituitary stem/progenitor cell function. Studies for Aim 2 will use unbiased polysome-based, RNA-sequencing approaches to test the hypothesis that Musashi has gender-specific mRNA targets and RNA-targeting mechanisms that control cell fate decisions in stem/progenitor cells and in adaptive responses of adult hormone-producing cell populations. The findings from this study will fully inform the field about the role of Musashi activity and mRNA translation in the control of pituitary cell plasticity and stem/progenitor cell function. Furthermore, these proposed studies relate to therapeutic approaches for endocrine and metabolic diseases, specifically caused by pituitary deficiencies. As hormone replacement strategies do not fully mimic physiological pulsatile secretion regimes, studies that promote regeneration of missing endocrine cell lineages would be a significant clinical improvement. This will positively impact gender-appropriate treatment paradigms for combined pituitary hormone deficiency, metabolic disease and pituitary tissue repair after head injury.