OTX1下游靶基因和神经发育障碍的分子机制研究

转录因子OTX1表达在发育期大脑皮质。在局部皮质发育不良的癫痫病人脑组织中OTX1表达异常。 而关联分析发现OTX1可能与自闭症谱系障碍有关。 但OTX1参与人类癫痫和自闭症形成的分子机制尚不清楚。我们发现Otx1在大脑皮质神经元的树突发育和电生理活动中起着重要作用。通过分析Otx1突变小鼠第五皮层神经元的基因表达，已发现钙离子激活的钾离子通道KCNN1可能受 Otx1的表达调控。KCNN1调节神经元兴奋性以及突触传递。 本项目将采用Otx1突变小鼠和胚胎基因转染技术, 研究 Otx1在正常和癫痫小鼠中对Kcnn1的表达调节。同时将证实Otx1调控神经元的树突形态，突触数目以及神经元兴奋性，并研究KCNN1在其中的介导作用。最后通过寻找OTX1在基因组的结合位点，以确定OTX1转录调控的下游靶基因。本课题将揭示癫痫和自闭症形成一个新的分子机制.

Transcription factor OTX1 is expressed in the developing cerebral cortex. The expression of OTX1 in the human brains with focal cortical dysplasia and epilepsy is abnormal. OTX1 has also been associated with autism and intellectual disability in cohorts of patients. However, the molecular processes underlying the roles of OTX1 in epilepsy and autism are unclear. We found in the previous studies that Otx1 plays important roles in the dendritic morphology and electrophysiology of cortical neurons. By comparing the gene expression of layer V cortical neurons between Otx1 mutant and the wild-type mice, we postulated that Ca2+-activated K+ channel Kcnn1 may subject to the regulation by Otx1. KCNN1 participates in hyperpolarization of action potential and regulates excitability of neurons and the excitatory neural transmission. By employing Otx1 mutant mice and in utero electroporation technique, this study will determine the expressional regulation of Kcnn1 by Otx1 in normal and epileptic mice. We will also examine Kcnn1-mediated Otx1 regulation of dendritic morphology, spine formation, and excitability of neurons. Finally, the transcriptional downstream targets of OTX1 will be determined by searching the binding sites of OTX1 in the genome. This study will reveal a novel molecular mechanism underlying the etiologies of autism and epilepsy.