Circadian Kinetics of Cell Cycle Progression in Adult Neurogenic Niches of a Diurnal Vertebrate.
Circadian Kinetics of Cell Cycle Progression in Adult Neurogenic Niches of a Diurnal Vertebrate.
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DOI：
10.1523/jneurosci.3222-16.2017
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发表时间：
2017-02-15
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影响因子：
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通讯作者：
Zhdanova IV
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文献类型：
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作者：
Akle V;Stankiewicz AJ;Kharchenko V;Yu L;Kharchenko PV;Zhdanova IV
昼夜节律系统可以通过细胞内分子钟机制或通过改变神经原性小生境的环境来调节成体神经发生，其中生长因子或营养物质的每日变化取决于动物的昼夜或夜间生活方式。在一个昼夜脊椎动物，斑马鱼，我们研究了昼夜分布的免疫组织化学标记的细胞分裂周期（CDC）在5的16个神经原性龛的成年大脑，背端脑，缰，视前区，下丘脑和小脑。我们发现，共同的所有龛是早上开始的G1/S转换和白天的S期进展，G2/M的夜间增加，并在深夜完成周期。这一点得到了脑组织中关键细胞周期调节因子细胞周期蛋白D、A2和B2以及细胞周期蛋白依赖性激酶抑制剂p20基因表达时间的支持。在p20，限制G1/S转换，其与核心时钟基因，Clock 1和Per 1的表达的相位角，在恒定的黑暗中保存，提示内在的昼夜节律模式的细胞周期进程。CDC动力学的统计建模揭示了在所有检查的小生境中细胞增殖速率的显著昼夜变化，但是在CDC的昼夜变化幅度、S-相长度、夹带到光或时钟的相位角及其分散方面存在interniche差异。我们的结论是，在成年昼夜脊椎动物的神经源性龛，昼夜节律的细胞周期进程的调制涉及系统和龛特异性因素。本研究证实，在成年昼行脊椎动物的神经原性小生境中，细胞周期进程显示出强有力的昼夜节律模式。位于不同脑区的神经原性小生境的共同点是白天DNA复制和夜间有丝分裂的进展，这表明系统性调节。神经源性小生境的阶段和程度的S-相夹带的时钟之间的差异表明小生境特异性调节机制的额外作用。了解成人神经发生的昼夜节律调节可以帮助优化脑创伤或神经退行性疾病患者的治疗方法的时机，并在细胞抑制癌症治疗期间保护神经干细胞。
The circadian system may regulate adult neurogenesis via intracellular molecular clock mechanisms or by modifying the environment of neurogenic niches, with daily variation in growth factors or nutrients depending on the animal's diurnal or nocturnal lifestyle. In a diurnal vertebrate, zebrafish, we studied circadian distribution of immunohistochemical markers of the cell division cycle (CDC) in 5 of the 16 neurogenic niches of adult brain, the dorsal telencephalon, habenula, preoptic area, hypothalamus, and cerebellum. We find that common to all niches is the morning initiation of G1/S transition and daytime S-phase progression, overnight increase in G2/M, and cycle completion by late night. This is supported by the timing of gene expression for critical cell cycle regulators cyclins D, A2, and B2 and cyclin-dependent kinase inhibitor p20 in brain tissue. The early-night peak in p20, limiting G1/S transition, and its phase angle with the expression of core clock genes, Clock1 and Per1, are preserved in constant darkness, suggesting intrinsic circadian patterns of cell cycle progression. The statistical modeling of CDC kinetics reveals the significant circadian variation in cell proliferation rates across all of the examined niches, but interniche differences in the magnitude of circadian variation in CDC, S-phase length, phase angle of entrainment to light or clock, and its dispersion. We conclude that, in neurogenic niches of an adult diurnal vertebrate, the circadian modulation of cell cycle progression involves both systemic and niche-specific factors. SIGNIFICANCE STATEMENT This study establishes that in neurogenic niches of an adult diurnal vertebrate, the cell cycle progression displays a robust circadian pattern. Common to neurogenic niches located in diverse brain regions is daytime progression of DNA replication and nighttime mitosis, suggesting systemic regulation. Differences between neurogenic niches in the phase and degree of S-phase entrainment to the clock suggest additional roles for niche-specific regulatory mechanisms. Understanding the circadian regulation of adult neurogenesis can help optimize the timing of therapeutic approaches in patients with brain traumas or neurodegenerative disorders and preserve neural stem cells during cytostatic cancer therapies.