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: 10358592
• 负责人: Sally A. Camper
• 金额: $ 43.21万
• 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/10358592
• 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; 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.

垂体性：Prop1和视黄酸信号传导在垂体干细胞调节中的作用 分化 抽象的 我们的总体目标是了解人类垂体不足（垂体不足）的分子基础 和老鼠。这个目标背后的理由是对这种常见先天缺陷的分子理解 影响1/4000名儿童将产生1）有关器官发生的基本信息，2）诊断具有价值 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 这可以帮助有先天性问题的儿童以及患有垂体功能障碍的成年人。突变 据报道，在三十个基因中会导致垂体不足和生长不足，但大多数患者 保持没有分子诊断。垂体特异性转录因子Prop1中的突变是最多的 人类中垂体不足的常见原因。 Prop1是层次结构中的第一个垂体特异性基因 调节垂体发展的转录因子。我们确定了Prop1的角色 垂体干细胞向上皮细胞中产生激素的细胞向间质样过渡的过渡 过程，这是器官发生和其他器官中侵入性癌的过渡的组成部分 系统。 Prop1的至少两个直接靶标会在突变时引起垂体不足，该基因编码该基因 转录因子POU1F1和HESX1。我们建议检验以下假设：1）Prop1具有 在垂体发展中双重作用。 prop1的胚胎表达对于驱动垂体置换是必要的 命运和抑制分化为不适当的细胞命运，而prop1的产后表达为 对于从干细胞池补充产生激素的细胞的重要性和2）Prop1需要 刺激视黄酸信号传导，该信号传导驱动干细胞过渡到区分POU1F1谱系， 3）干细胞表达分析将揭示调节器官的新型候选基因和途径 开发和维护，并为垂直症病例提供候选基因，尚无已知 诊断。我们将在小鼠模型中进行功能研究，并应用最先进的单个单元格 测序技术，揭示了prop1和视黄酸信号传导在垂体发展和 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，并有助于更好地理解造成遗传和环境因素 垂体激素缺乏症。