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育潜力，允许它们扩增干细胞的输出，但其潜力如何建立仍然未知。在果蝇幼虫大脑中，trimm - nhl蛋白脑肿瘤（Brat）是中间神经祖细胞（INPs）形成所必需的，但其机制存在争议。在这里，我们发现Brat通过进化保守的b -box诱导分化和抑制去分化，在未成熟的INP中建立了限制性电位。Brat通过促进未成熟INP中转录激活因子PointedP1的核定位诱导分化，其中PointedP1通过一种新的受体酪氨酸激酶独立机制触发及时分化。此外，Brat通过维持大肠腺瘤性息肉病2蛋白的表达和拮抗独立于受体Frizzled的-catenin的功能，抑制未成熟INP的去分化。因此，Brat通过限制INP的发育潜力来促进有丝分裂后后代的产生，并防止异常祖细胞的积累。鉴于所有TRIM家族蛋白都含有至少一个B-box， Brat限制INP发育潜力的机制可能与其他干细胞谱系有关，并可能为中间祖细胞的去调控引起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.