Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India.
Mol Neurobiol. 2018 Feb;55(2):936-945. doi: 10.1007/s12035-016-0359-4. Epub 2017 Jan 13.
Differentiation of neural stem cells (NSC's) to mature and functional neurons requires coordinated expression of mRNA, microRNAs (miRNAs) and regulatory proteins. Our earlier unbiased miRNA profiling studies have identified miR-200, miR-34 and miR-221/222 as maximally up-regulated miRNA families in differentiating PC12 cells and demonstrated the capability of miR-200 family in inducing neuronal differentiation (J. Neurochem, 2015, 133, 640-652). In present study, we have investigated role of miR-34 family in neuronal differentiation and identified P53 as mediator of nerve growth factor (NGF) induced miR-34a expression in differentiating PC12 cells. Our studies have shown that NGF induced miR-34a, arrests proliferating PC12 cells to G1 phase, which is pre-requisite for neuronal differentiation. Our studies have also shown that increased expression of miR-34a controls the P53 level in differentiated PC12 cells in feedback inhibition manner, which probably prevents differentiated cells from P53 induced apoptosis. Expression profiling of miR-34 family in different neuronal, non-neuronal and developing cells have identified differentiated and aged brain cells as richest source of miR-34, which also indicates that higher expression of miR-34 family helps in maintaining the mature neurons in non-proliferative stage. In conclusion, our studies have shown that miR-34 is brain enriched miRNA family, which up-regulates with neuronal maturation and brain ageing and co-operative regulation of P53 and miR-34a helps in neuronal differentiation by arresting cells in G1 phase.
神经干细胞（NSC）向成熟和功能神经元的分化需要协调 mRNA、microRNAs（miRNAs）和调节蛋白的表达。我们之前的无偏 miRNA 谱分析研究已经确定了 miR-200、miR-34 和 miR-221/222 是分化的 PC12 细胞中上调最明显的 miRNA 家族，并证明了 miR-200 家族在诱导神经元分化中的能力（J. Neurochem, 2015, 133, 640-652）。在本研究中，我们研究了 miR-34 家族在神经元分化中的作用，并确定了 P53 是神经生长因子（NGF）诱导分化的 PC12 细胞中 miR-34a 表达的介导物。我们的研究表明，NGF 诱导的 miR-34a 将增殖的 PC12 细胞阻滞在 G1 期，这是神经元分化的必要条件。我们的研究还表明，miR-34a 的表达增加以反馈抑制的方式控制分化的 PC12 细胞中的 P53 水平，这可能防止分化的细胞发生 P53 诱导的细胞凋亡。miR-34 家族在不同神经元、非神经元和发育细胞中的表达谱分析表明，分化和衰老的脑细胞是 miR-34 的最丰富来源，这也表明 miR-34 家族的高表达有助于维持成熟神经元处于非增殖状态。总之，我们的研究表明，miR-34 是富含大脑的 miRNA 家族，随着神经元的成熟和大脑的衰老而上调，P53 和 miR-34a 的协同调节有助于通过将细胞阻滞在 G1 期来促进神经元分化。
