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。

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.