Nkx2.1对5-HT3AR/Sox6双阳性中间神经元发生发育的调控作用和机制

兴奋性和抑制性的动态平衡对大脑发挥正常功能至关重要。5-HT3AR+中间神经元是构建大脑神经网络，维持该动态平衡的关键细胞，其发育缺陷可引发多种神经系统疾病，但是目前对于5-HT3AR+中间神经元发生发育和相关调控机制尚不明确。申请者预实验发现：成年小鼠脑内存在一类5-HT3AR/Sox6双阳性中间神经元，而在胚胎发育时期，小鼠内侧基底神经节隆起和视前区存在5-HT3AR/Nkx2.1双阳性的中间神经元前体细胞。文献显示：Nkx2.1是Sox6的上游基因。据此提出假设：5-HT3AR/Sox6双阳性中间神经元可能起源于内侧基底神经节隆起或视前区，其发生发育可能受Nkx2.1的调控。为证实这一假设，本项目将以转基因和条件性基因敲除小鼠为研究对象，研究5-HT3AR+/Sox6+中间神经元的发生发育，探索Nkx2.1对其发生发育的调控机制,为研发治疗相关疾病理想药物提供新靶点。

The balance between excitation and inhabitation is crucial for brain function. 5-HT3AR positive interneurons play a key role in constructing the cerebral neural network and keeping the balance between excitation and inhibition. It is widely accepted that their developmental defects could cause a variety of neurological disorders. However, the development and molecular mechanisms of 5-HT3AR positive interneurons are not fully understood. Our preliminary data demonstrates that there is a class of 5-HT3AR/Sox6 double-positive interneurons in the adult mouse brain, while there is a class of 5-HT3AR/ Nkx2.1 double-positive precursor cells in mouse medial basal ganglionic eminence and the preoptic area at the stage of embryonic development. Literature shows that Nkx2.1 is the upstream gene of Sox6. On the basis of these findings, we propose the hypothesis that 5-HT3AR/Sox6 double-positive interneurons may be derived from the medial ganglionic eminences and/or the preoptic area and Nkx2.1 could play a important role in the development of the 5-HT3AR/Sox6 double-positive interneurons. To substantiate this hypothesis, the present project aims to elucidate the development of the 5-HT3AR/Sox6 double-positive interneurons and to investigate the regulation of Nkx2.1 in their development using transgenic and conditional knockout mice. This project will shed light on new targets for drug discovery.