Brain tumor restricts developmental potential in intermediate progenitor cells

脑肿瘤限制中间祖细胞的发育潜力

• 批准号: 8268040
• 负责人: Cheng-Yu Lee
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268040
• 关键词: Adenomatous Polyposis Coli; Adopted; Binding; Boxing; Brain; Brain Neoplasms; Cell Lineage; Cell Maintenance; Cells; Coiled-Coil Domain; Data; Development; Drosophila genus; Equilibrium; Exhibits; Failure; Generations; Genes; Genetic Screening; Genomics; Homeostasis; Ions; Lead; Maintenance; Malignant Neoplasms; Mediating; Medicine; Mitotic; Molecular; Nuclear; Output; Pattern; Play; Process; Property; Proteins; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Regulation; Role; Stem cells; Structure; TRIM Family; TRIM Gene; Testing; Tissues; Transcription Coactivator; Transcriptional Activation; Zinc; fly; gene repression; in vivo; insight; nerve stem cell; neuroblast; neurogenesis; novel; oncology; prevent; progenitor; protein expression; receptor; stem; tumor; tumor initiation

DESCRIPTION (provided by applicant): Intermediate progenitor cells possess restricted developmental potential allowing them to amplify the output of stem cells, but how their potential is established remains unknown. In the Drosophila larval brain, the TRIM-NHL protein Brain tumor (Brat) is required for formation of intermediate neural progenitors (INPs), but the mechanisms are controversial. Here, we show that Brat establishes restricted potential in the immature INP by inducing differentiation and suppressing de-differentiation via the evolutionarily conserved B-boxes. Brat induces differentiation by promoting nuclear localization of the transcriptional activator PointedP1 in the immature INP, where PointedP1 triggers timely differentiation via a novel receptor tyrosine kinase-independent mechanism. Furthermore, Brat suppresses de-differentiation of the immature INP by maintaining expression of the Adenomatous polyposis coli 2 protein and antagonizing the function of the ¿-catenin independently of the receptor Frizzled. Thus, Brat promotes generation of post-mitotic progeny and prevents accumulation of aberrant progenitors by restricting the developmental potential in the INP. Giving all TRIM family proteins contain at least one B-box, the mechanism by which Brat restricts the developmental potential in the INP might be relevant to other stem cell lineages, and will likely provide novel mechanistic insight into tumors arisen from de-regulation of intermediate progenitor cells. PUBLIC HEALTH RELEVANCE: Many types of stem cells generate intermediate progenitor cells that exhibit restricted developmental potential and generate differentiated progeny protecting the genomic integrity of the stem cell pool. Failure to properly restrict the potential n intermediate progenitor cells can lead to reduction in differentiated cells and accumulation of aberrant stem-like cells resulting in loss of tissue homeostasis and development of malignancy. The TRIM-NHL protein Brain tumor establishes restricted potential in the neural progenitor cell in the fly larval brain by the combination of promoting differentiation and suppressing de-differentiation. The Brain tumor dependent process provides a novel mechanism to distinguish stem cells from intermediate progenitor cells and suppress tumors arisen from de-regulation of intermediate progenitor cells.

描述（由适用提供）：中间祖细胞的潜在限制发育潜力，使它们可以扩增干细胞的输出，但是如何确定其电位仍然未知。在果蝇幼虫大脑中，形成中间神经祖细胞（INPS）需要修剪NHL蛋白脑肿瘤（BRAT），但机制是有争议的。在这里，我们表明，小子通过通过进化配置的B盒诱导分化和抑制脱不同的限制来在未成熟的INP中建立受限的潜力。小子通过促进未成熟INP中转录激活剂的核定位来诱导分化，在该INP中，尖头启动的PointEDP1通过新型受体酪氨酸激酶非依赖性机制触发及时的分化。此外，小子通过维持腺瘤性息肉病大肠杆菌2蛋白的表达来抑制未成熟INP的去分化，并与受体毛皮独立于受体的功能拮抗 - 卡宁蛋白的功能。这是小子促进有丝分裂后后代的产生，并通过限制INP的发育潜力来防止异常祖细胞的积累。给出所有修剪家族蛋白至少包含一个B盒，Brat限制INP的发育潜力的机制可能与其他干细胞谱系有关，并且可能会提供新的机械洞察力，以使其对中间祖细胞的下调产生的肿瘤产生。 公共卫生相关性：许多类型的干细胞产生中间祖细胞，这些细胞耗尽了限制发育潜力并产生分化的后代，以保护干细胞库的基因组完整性。不正确限制潜在的N中间祖细胞会导致分化细胞的降低和异常的干细胞的积累，从而导致组织稳态丧失和恶性肿瘤的发展。 TRIM-NHL蛋白脑肿瘤通过促进分化和抑制脱不同的二分化，在蝇幼虫脑中神经祖细胞中建立了受限的潜力。脑肿瘤依赖性过程提供了一种新的机制，可以将干细胞与中间祖细胞区分开并抑制因中间祖细胞的下调而引起的肿瘤。