Hypopituitarism: role of PROP1 and retinoic acid signaling in regulation of pituitary stem cell differentiation

垂体功能减退症：PROP1和维甲酸信号在垂体干细胞调节中的作用 分化 摘要 我们的首要目标是了解人类垂体功能不全(垂体功能减退)的分子基础。 还有老鼠。这一目标背后的理论基础是，对这种常见出生缺陷的分子理解 影响1/4000儿童将产生1)器官发生的基本信息，2)有价值的诊断 用于预测风险和监测进展，以及3)最终提供关于治疗方法的见解 这可以帮助患有先天性问题的儿童和患有后天性垂体功能障碍的成年人。突变 据报道，有30个基因会导致垂体腺功能减退和生长不全，然而大多数患者 仍然没有分子诊断。脑垂体特异转录因子PROP1的突变最多 人类垂体功能减退的常见原因。Prop1是该层级中第一个脑垂体特异性基因 调节脑下垂体发育的转录因子。我们确立了Prop1在调节 上皮样向间充质样转化中垂体干细胞向激素分泌细胞的转化 过程，这是器官发生和向其他器官的浸润性癌症过渡的一个组成部分 系统。Prop1的至少两个直接靶点在突变时会导致垂体功能低下，编码Prop1的基因 转录因子POU1F1和HESX1。我们建议检验以下假设：1)PROP1具有 在脑下垂体发育中的双重作用。Prop1在胚胎中的表达是驱动垂体胎盘发育所必需的 命运和抑制分化为不适当的细胞命运，而Prop1在出生后表达 对于从干细胞库补充产生激素的细胞很重要，以及2)PROP1被要求 刺激维甲酸信号，驱动干细胞过渡分化为POU1F1谱系， 3)干细胞表达谱将揭示新的候选基因和调控器官的途径 发育和维持，并为未知的垂体功能减退症病例提供候选基因。 诊断。我们将在小鼠模型中进行功能研究，并应用最先进的单细胞 测序技术，揭示PROP1和维甲酸信号在垂体发育和 功能。这些目标的完成将提供有关垂体前体细胞生成的基本信息 和扩散，并有助于更好地了解有助于 脑下垂体激素缺乏症。

Hypopituitarism: role of PROP1 and retinoic acid signaling in regulation of pituitary stem cell differentiation Abstract Our overarching goal is to understand the molecular basis of pituitary insufficiency (hypopituitarism) in humans and mice. The rationale behind this goal is that a molecular understanding of this common birth defect affecting 1/4000 children will yield 1) fundamental information about organogenesis, 2) diagnoses with value for predicting risk and monitoring progression, and 3) ultimately provide insight about therapeutic approaches that could aid children with congenital problems as well as adults with acquired pituitary dysfunction. Mutations in thirty genes are reported to cause hypopituitarism and growth insufficiency, yet the majority of the patients remain with no molecular diagnosis. Mutations in the pituitary-specific transcription factor PROP1 are the most common known cause of hypopituitarism in humans. Prop1 is the first pituitary-specific gene in the hierarchy of transcription factors that regulate pituitary development. We established a role for Prop1 in regulating the transition of pituitary stem cells to hormone-producing cells in an epithelial to mesenchymal-like transition process, which is a component of both organogenesis and the transition to invasive cancer in other organ systems. At least two direct targets of Prop1 cause hypopituitarism when mutated, the genes encoding the transcription factors POU1F1 and HESX1. We propose to test the following hypotheses: 1) PROP1 has a dual role in pituitary development. Embryonic expression of Prop1 is necessary for driving pituitary placode fate and suppressing differentiation into inappropriate cell fates, while postnatal expression of Prop1 is important for replenishment of hormone-producing cells from stem cell pools, and 2) PROP1 is required to stimulate retinoic acid signaling, which drives stem cells to transition to differentiate into the POU1F1 lineage, and 3) stem cell expression profiling will reveal novel candidate genes and pathways that regulate organ development and maintenance, and provide candidate genes for cases of hypopituitarism with no known diagnosis. We will conduct functional studies in mouse models and apply state of the art single cell sequencing technology, revealing the roles of PROP1 and retinoic acid signaling in pituitary development and function. Completion of these goals will provide fundamental information on pituitary precursor cell generation and proliferation and contribute to better understanding of the genetic and environmental factors that contribute to pituitary hormone deficiency.