Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors
Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors
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DOI：
10.1242/dev.106534
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发表时间：
2014-03-01
期刊：
影响因子：
4.6
通讯作者：
Lee, Cheng-Yu
中科院分区：
文献类型：
--
作者：
Janssens, Derek H.;Komori, Hideyuki;Lee, Cheng-Yu
尽管表达干细胞自我更新因子，但中间祖细胞具有有限的发育潜力，这使得它们只能产生分化的后代而不是干细胞后代。未能限制发育潜力可能会使中间祖细胞恢复为可能导致肿瘤发生的异常干细胞。对中间祖细胞发育潜能的稳定限制的了解可以提高我们对肿瘤发展和生长的理解，但所涉及的机制在很大程度上仍然未知。中间神经祖细胞（INPs），产生的II型神经干细胞（神经母细胞）在苍蝇幼虫的大脑，提供了一个体内模型，研究机制，稳定限制中间祖细胞的发育潜力。在这里，我们报告说，转录抑制蛋白耳罩（Erm）功能暂时脑肿瘤（布拉特）和Numb后，限制未提交（未成熟）INPs的发展潜力。一致地，内源性Erm在未成熟的INPs中检测到，但在INPs中检测不到。不成熟INPs的发育潜能的Erm依赖性限制导致INPs对所有已知的成神经细胞自我更新因子的反应能力减弱。我们还发现，BAP染色质重塑复合物可能与Erm合作，限制未成熟INPs的发育潜力。总之，这些数据使我们得出结论，Erm-BAP依赖性机制通过减弱未成熟INPs对干细胞自我更新因子的基因组反应来稳定地限制其发育潜力。我们提出，Erm-BAP依赖性机制对发育潜能的限制在功能上区分了中间祖细胞和干细胞，确保了分化细胞的产生并防止了祖细胞衍生的肿瘤起始干细胞的形成。
Despite expressing stem cell self-renewal factors, intermediate progenitor cells possess restricted developmental potential, which allows them to give rise exclusively to differentiated progeny rather than stem cell progeny. Failure to restrict the developmental potential can allow intermediate progenitor cells to revert into aberrant stem cells that might contribute to tumorigenesis. Insight into stable restriction of the developmental potential in intermediate progenitor cells could improve our understanding of the development and growth of tumors, but the mechanisms involved remain largely unknown. Intermediate neural progenitors (INPs), generated by type II neural stem cells (neuroblasts) in fly larval brains, provide an in vivo model for investigating the mechanisms that stably restrict the developmental potential of intermediate progenitor cells. Here, we report that the transcriptional repressor protein Earmuff (Erm) functions temporally after Brain tumor (Brat) and Numb to restrict the developmental potential of uncommitted (immature) INPs. Consistently, endogenous Erm is detected in immature INPs but undetectable in INPs. Erm-dependent restriction of the developmental potential in immature INPs leads to attenuated competence to respond to all known neuroblast self-renewal factors in INPs. We also identified that the BAP chromatin-remodeling complex probably functions cooperatively with Erm to restrict the developmental potential of immature INPs. Together, these data led us to conclude that the Erm-BAP-dependent mechanism stably restricts the developmental potential of immature INPs by attenuating their genomic responses to stem cell self-renewal factors. We propose that restriction of developmental potential by the Erm-BAP-dependent mechanism functionally distinguishes intermediate progenitor cells from stem cells, ensuring the generation of differentiated cells and preventing the formation of progenitor cell-derived tumor-initiating stem cells.