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.

垂体功能减退：PROP1和维甲酸信号在垂体干细胞调控中的作用