Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599, USA.
Cell Rep. 2016 Jan 12;14(2):216-24. doi: 10.1016/j.celrep.2015.12.037. Epub 2015 Dec 31.
Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells.
维持基因组完整性在神经发育过程中至关重要，尤其是在经历组成性复制相关 DNA 损伤的快速分裂的小脑颗粒神经元前体细胞中。由于最近发现 Dicer 在 DNA 损伤反应中具有意想不到的功能，我们研究了 Dicer 是否对发育中的大脑中基因组完整性的维持很重要。我们报告说，在发育中的小鼠小脑中敲除 Dicer 会导致 DNA 损伤积累，从而导致小脑前体细胞退化，而 p53 缺失可以挽救这一过程；敲除 DGCR8 也会导致类似的 DNA 损伤和小脑退化。Dicer 缺陷也会导致其他快速分裂的细胞（包括胚胎干细胞和 Medulloblastoma 小鼠模型中的恶性小脑前体细胞）中的 DNA 损伤和死亡。总之，这些结果表明 Dicer 在解决发育中的祖细胞和恶性细胞快速增殖过程中自发产生的 DNA 损伤方面具有重要功能。
