Williams Alison A, White Robin, Siniard Ashley, Corneveaux Jason, Huentelman Matt, Duch Carsten
School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA; Institute of Zoology- Neurobiology, Johannes Gutenberg University Mainz, 55128, Germany.
Institute of Physiology, University Medical Center, Mainz 55128, Germany.
Neurobiol Dis. 2016 Jul;91:284-91. doi: 10.1016/j.nbd.2016.03.019. Epub 2016 Mar 22.
Using a Drosophila model of MECP2 gain-of-function, we identified memory associated KIBRA as a target of MECP2 in regulating dendritic growth. We found that expression of human MECP2 increased kibra expression in Drosophila, and targeted RNAi knockdown of kibra in identified neurons fully rescued dendritic defects as induced by MECP2 gain-of-function. Validation in mouse confirmed that Kibra is similarly regulated by Mecp2 in a mammalian system. We found that Mecp2 gain-of-function in cultured mouse cortical neurons caused dendritic impairments and increased Kibra levels. Accordingly, Mecp2 loss-of-function in vivo led to decreased Kibra levels in hippocampus, cortex, and cerebellum. Together, our results functionally link two neuronal genes of high interest in human health and disease and highlight the translational utility of the Drosophila model for understanding MECP2 function.
利用MECP2功能获得性的果蝇模型，我们确定了与记忆相关的KIBRA是MECP2调节树突生长的一个靶点。我们发现，人类MECP2的表达增加了果蝇中kibra的表达，并且在已确定的神经元中靶向RNA干扰敲低kibra可完全挽救由MECP2功能获得所诱导的树突缺陷。在小鼠中的验证证实，在哺乳动物系统中Kibra同样受Mecp2调控。我们发现，在培养的小鼠皮质神经元中Mecp2功能获得会导致树突损伤并增加Kibra水平。相应地，体内Mecp2功能丧失会导致海马体、皮质和小脑中Kibra水平降低。总之，我们的结果在功能上连接了人类健康和疾病中两个备受关注的神经元基因，并突出了果蝇模型在理解MECP2功能方面的转化应用价值。
