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：PROP 1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的儿童将产生1）关于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人。突变 据报道，30个基因中有10个基因导致垂体功能减退和生长不足，但大多数患者 仍然没有分子诊断。垂体特异性转录因子PROP 1的突变是最常见的。 是人类垂体功能减退的常见原因。Prop 1是第一个垂体特异性基因 调节垂体发育的转录因子。我们确定了Prop 1在调节 垂体干细胞在上皮细胞向间充质样细胞的转化中向分泌细胞的转化 过程，这是器官发生和向其他器官中的侵袭性癌症转变的组成部分 系统. Prop 1的至少两个直接靶点突变时会导致垂体功能减退，编码 转录因子POU 1F 1和HESX 1。我们建议测试以下假设：1）PROP 1具有 垂体发育的双重作用。Prop 1在胚胎中的表达是驱动垂体基板所必需的 命运和抑制分化成不适当的细胞命运，而出生后表达的Prop 1是 对于从干细胞库中补充产生干细胞的细胞是重要的，以及2）PROP 1需要 刺激视黄酸信号传导，其驱动干细胞转变以分化成POU 1F 1谱系， 3）干细胞表达谱将揭示新的候选基因和调控器官功能的途径。 发展和维护，并提供候选基因的情况下，垂体功能减退症，没有已知的 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PROP 1和视黄酸信号在垂体发育中的作用， 功能这些目标的完成将为垂体前体细胞的生成提供基础信息 并有助于更好地了解遗传和环境因素， 垂体激素缺乏症