Valli Emanuele, Trazzi Stefania, Fuchs Claudia, Erriquez Daniela, Bartesaghi Renata, Perini Giovanni, Ciani Elisabetta
Department of Pharmacy and Biotechnology, University of Bologna, Italy.
Biochim Biophys Acta. 2012 Nov-Dec;1819(11-12):1173-85. doi: 10.1016/j.bbagrm.2012.08.001. Epub 2012 Aug 19.
Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene are associated with a severe epileptic encephalopathy (early infantile epileptic encephalopathy type 2, EIEE2) characterized by early-onset intractable seizures, infantile spasms, severe developmental delay, intellectual disability, and Rett syndrome (RTT)-like features. Despite the clear involvement of CDKL5 mutations in intellectual disability, the function of this protein during brain development and the molecular mechanisms involved in its regulation are still unknown. Using human neuroblastoma cells as a model system we found that an increase in CDKL5 expression caused an arrest of the cell cycle in the G(0)/G(1) phases and induced cellular differentiation. Interestingly, CDKL5 expression was inhibited by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology. Through a combination of different and complementary molecular and cellular approaches we could show that MYCN acts as a direct repressor of the CDKL5 promoter. Overall our findings unveil a functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation. The fact that CDKL5 is involved in the control of both neuron proliferation and differentiation may help understand the early appearance of neurological symptoms in patients with mutations in CDKL5.
细胞周期蛋白依赖性激酶样5（CDKL5）基因突变与一种严重的癫痫性脑病（早发性婴儿癫痫性脑病2型，EIEE2）相关，其特征为早发性难治性癫痫发作、婴儿痉挛、严重发育迟缓、智力残疾以及类瑞特综合征（RTT）特征。尽管CDKL5突变明显与智力残疾有关，但该蛋白在大脑发育过程中的功能及其调控所涉及的分子机制仍不清楚。我们以人神经母细胞瘤细胞作为模型系统，发现CDKL5表达增加会导致细胞周期停滞在G(0)/G(1)期并诱导细胞分化。有趣的是，CDKL5的表达受到MYCN的抑制，MYCN是一种转录因子，在大脑发育过程中促进细胞增殖，并且在神经母细胞瘤生物学中发挥相关作用。通过结合不同且互补的分子和细胞方法，我们能够证明MYCN作为CDKL5启动子的直接抑制因子发挥作用。总体而言，我们的研究结果揭示了MYCN和CDKL5之间的一个功能轴，该轴调控神经元增殖速率和分化。CDKL5参与神经元增殖和分化的控制这一事实，可能有助于理解CDKL5基因突变患者神经症状的早期出现。
