Yasugi Tetsuo, Fischer Anja, Jiang Yanrui, Reichert Heinrich, Knoblich Juergen A
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
Biozentrum, University of Basel, Basel, Switzerland.
PLoS One. 2014 May 7;9(5):e97034. doi: 10.1371/journal.pone.0097034. eCollection 2014.
Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis.
神经发生由一组基本的螺旋-环-螺旋（bHLH）转录因子启动，这些转录因子指定神经祖细胞，并使其能够在多轮不对称细胞分裂中产生神经元。果蝇的无女儿（Da）蛋白及其哺乳动物对应物（E12/E47）作为神经原性基因的异二聚化因子，因此是神经发生所必需的。在这里，我们证明Da也可以是神经祖细胞命运的抑制剂，其缺失会导致干细胞过度增殖和肿瘤形成。我们通过证明Da诱导分化因子Prospero（Pros）来解释这一矛盾，其不对称分离对于两个子细胞之一的分化至关重要。Da与bHLH转录因子Asense合作，而其他神经原性基因则是可有可无的。有丝分裂后，Pros在两个子细胞之一中终止Asense的表达。在da突变体中，pros不表达，导致形成致命的可移植脑肿瘤。我们的结果定义了一个转录反馈环，该反馈环调节果蝇视叶神经母细胞自我更新和分化之间的平衡。它们表明干细胞中神经分化程序的启动对于预防肿瘤发生至关重要。
