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: 8837708
• 负责人: Cheng-Yu Lee
• 金额: $ 33.45万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837708
• 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; 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; genome integrity; 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.

描述（由申请人提供）：中间祖细胞具有有限的发育潜力，允许它们放大干细胞的输出，但它们的潜力如何在果蝇幼虫大脑中建立仍然未知。中间神经祖细胞（INP）的形成是必需的，但其机制存在争议，在这里，我们证明 Brat 通过诱导分化和抑制在未成熟的 INP 中建立限制性潜力。 Brat 通过促进未成熟 INP 中转录激活因子 PointedP1 的核定位来诱导分化，其中 PointedP1 通过一种新型受体酪氨酸激酶独立机制触发及时分化。通过维持腺瘤性息肉病大肠杆菌 2 蛋白的表达并拮抗 ¿ 的功能来抑制未成熟的 INP因此，Brat 可以通过限制 INP 的发育潜力来促进有丝分裂后后代的产生，并防止异常祖细胞的积累，从而使所有 TRIM 家族蛋白都含有至少一个 B 盒。 Brat 限制 INP 的发育潜力可能与其他干细胞谱系有关，并且可能为中间祖细胞失调引起的肿瘤提供新的机制见解。