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

垂体功能减退症：PROP1 和视黄酸信号在垂体干细胞分化调节中的作用

• 批准号: 9884806
• 负责人: Sally A. Camper
• 金额: $ 44.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-04 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884806
• 关键词: Adoption; Adult; Affect; Animals; Automobile Driving; Birth; Brain; Candidate Disease Gene; Cell Line; Cells; Cephalic; Child; Combined Modality Therapy; Congenital Abnormality; Craniofacial Abnormalities; Defect; Development; Diagnosis; Disease; Dominant-Negative Mutation; Doxycycline; Ectopic Expression; Embryo; Environmental Risk Factor; Enzymes; Epithelial; Epithelium; Ethanol; Exhibits; Exposure to; Expression Profiling; Fertility; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Holoprosencephaly; Hormones; Human; Hypopituitarism; In Situ Hybridization; Intellectual functioning disability; Knowledge; Maintenance; Maternal Exposure; Mesenchymal; Minor; Molecular; Molecular Diagnosis; Monitor; Mus; Mutant Strains Mice; Mutate; Mutation; Organ; Organogenesis; Pathway interactions; Patients; Phenotype; Physiological; Pituitary Diseases; Pituitary Gland; Pituitary Hormones; Predictive Value; Process; Prolactin; Regulation; Regulatory Pathway; Reporting; Risk; Role; SHH gene; Septo-Optic Dysplasia; Severities; Signal Transduction; Somatotropin; Stains; Syndrome; Technology; Testing; Therapeutic; Thyrotropin; Toxic Environmental Substances; Transgenic Mice; Tretinoin; Vitamin A; Vitamin A Deficiency; Work; adenoma; biological adaptation to stress; body system; cancer invasiveness; cell motility; cell type; hormone deficiency; improved; innovative technologies; insight; mouse model; mutant; neurosensory; novel; organ growth; pituitary gland development; postnatal; precursor cell; prenatal; protein expression; response; retinaldehyde dehydrogenase; single cell sequencing; stem cell biology; stem cell differentiation; stem cells; transcription factor

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.

垂体功能减退症：PROP1 和视黄酸信号在垂体干细胞调节中的作用 差异化 抽象的 我们的首要目标是了解人类垂体功能不全（垂体功能减退症）的分子基础 和老鼠。这一目标背后的基本原理是对这种常见出生缺陷的分子理解 影响 1/4000 名儿童将产生 1) 有关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，3) 最终提供有关治疗方法的见解 这可以帮助患有先天性问题的儿童以及患有后天性垂体功能障碍的成年人。突变 据报道，有 30 个基因会导致垂体机能减退和生长不足，但大多数患者 仍然没有分子诊断。垂体特异性转录因子 PROP1 的突变是最常见的。 人类垂体功能减退症的常见原因。 Prop1 是层次结构中第一个垂体特异性基因 调节垂体发育的转录因子。我们为 Prop1 设立了监管角色 垂体干细胞在上皮间质样转变中向激素产生细胞的转变 过程，是器官发生和其他器官向侵袭性癌症转变的一个组成部分 系统。 Prop1 的至少两个直接靶点突变时会导致垂体功能减退，即编码 转录因子 POU1F1 和 HESX1。我们建议测试以下假设：1）PROP1 有一个 在垂体发育中发挥双重作用。 Prop1 的胚胎表达对于驱动垂体基板是必需的 命运并抑制分化为不适当的细胞命运，而 Prop1 的出生后表达是 对于补充干细胞池中产生激素的细胞很重要，并且 2) PROP1 是必需的 刺激视黄酸信号传导，驱动干细胞转变分化为 POU1F1 谱系， 3）干细胞表达谱将揭示调节器官的新候选基因和途径 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，揭示了 PROP1 和视黄酸信号在垂体发育和 功能。这些目标的完成将为垂体前体细胞生成提供基本信息 和增殖，并有助于更好地了解导致遗传和环境因素 导致垂体激素缺乏。