Brain tumor restricts developmental potential in intermediate progenitor cells

描述(由申请人提供)：中间祖细胞具有有限的发展潜力，允许它们放大干细胞的输出，但它们的潜力是如何建立的仍不清楚。在果蝇幼虫脑中，TRIM-NHL蛋白脑瘤(BRAT)是形成中间神经前体细胞(INPs)所必需的，但其机制存在争议。在这里，我们发现Brat通过在进化上保守的B-box诱导分化和抑制去分化，在未成熟的INP中建立了限制潜能。Brat通过促进转录激活子PointdP1在未成熟INP中的核定位来诱导分化，其中PointedP1通过一种新的受体酪氨酸激酶不依赖的机制触发及时的分化。此外，Brat通过维持腺瘤性息肉病Coli2蛋白的表达，并独立于Frizzled受体拮抗β-连环蛋白的功能，抑制未成熟INP的去分化。因此，Brat通过限制INP的发育潜力，促进有丝分裂后后代的产生，并防止异常祖细胞的积累。由于所有TRIM家族蛋白至少包含一个B-box，Brat限制INP中的发育潜力的机制可能与其他干细胞谱系有关，并可能为解除中间前体细胞调控而产生的肿瘤提供新的机制见解。 与公共卫生相关：许多类型的干细胞产生的中间祖细胞表现出有限的发育潜力，并产生分化的后代，保护干细胞库的基因组完整性。如果不能适当地限制潜在的n个中间前体细胞，可能会导致分化细胞减少和异常干细胞样细胞的聚集，从而导致组织动态平衡的丧失和恶性肿瘤的发展。TRIM-NHL蛋白脑瘤通过促进分化和抑制去分化的结合，在苍蝇幼虫脑内的神经前体细胞中建立了限制潜能。脑肿瘤依赖过程提供了一种新的机制来区分干细胞和中间前体细胞，并抑制由于中间前体细胞去调节而产生的肿瘤。

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.