Transcriptional Control of Region-Specific Astrocyte Functions in Spinal Cord Circuits

项目总结 星形胶质细胞对中枢神经回路的产生、维持和功能是必不可少的。 神经系统(CNS)。我们实验室最近的研究表明，星形胶质细胞表现出广泛的 中枢神经系统几个区域的分子和功能多样性。要了解这一功能如何 多样性是编码的，我们鉴定了几个表现出区域特异性表达的转录因子(TF)。 尽管有这些发现，但在很大程度上，转铁蛋白对星形胶质细胞的生理和回路功能的贡献仍然存在。 未定义。在呈现区域特异性表达的TF中，我们发现同源盒Tf Nkx6.1是 仅在成熟脊髓腹侧星形胶质细胞中表达。Nkx6.1的时间条件删除 从成熟星形胶质细胞(Nkx6.1-CKO)获得的结果显示，腹侧星形胶质细胞的形态复杂性较低 脊髓提示它调节这些星形胶质细胞群体的关键特性。此外，马达 Nkx6.1-CKO脊髓神经元胆碱乙酰转移酶表达降低 伴有VGlut1突触数量减少。最后，CHIP-SEQ分析表明Nkx6.1结合， 并可能调节与细胞形态、神经元-星形胶质细胞通讯有关的基因表达， 以及突触的维护。总之，这些结果表明Nkx6.1维持着成熟的星形胶质细胞功能 它们对于维持脊髓中的突触回路是必不可少的。因此，我们建议的重点是： 1)确定Nkx6.1如何维持脊髓腹侧星形胶质细胞的形态和生理；2) 描绘依赖Nkx6.1的星形胶质细胞功能如何促进脊髓运动神经元和 3)明确Nkx6.1在脊髓腹侧调控的独特转录机制 脊髓星形胶质细胞。

PROJECT SUMMARY Astrocytes are essential for the generation, maintenance, and function of neuronal circuits in the central nervous system (CNS). Recent studies from our laboratory revealed that astrocytes exhibit extensive molecular and functional diversity across several regions of the CNS. To understand how this functional diversity is encoded, we identified several transcription factors (TFs) that exhibit region-specific expression. Despite these findings, how TFs contribute to astrocyte physiology and circuit function remain largely undefined. Among the TFs exhibiting region-specific expression, we found that the homeobox TF Nkx6.1 is expressed exclusively in ventral astrocytes of the mature spinal cord. Temporal-conditional deletion of Nkx6.1 from mature astrocytes (Nkx6.1-cKO) resulted in a lower morphological complexity of astrocytes in the ventral spinal cord suggesting that it regulates key properties of these astrocyte populations. Additionally, motor neurons from Nkx6.1-cKO spinal cords demonstrate reduced expression of choline acetyltransferase accompanied by reduced number of VGlut1 synapses. Finally, ChIP-seq analysis shows that Nkx6.1 binds, and possibly regualtes the expression of genes involved in cell morphology, neuron-astrocyte communication, and synaptic maintenance. Together, these results suggest that Nkx6.1 maintains mature astrocyte functions that are essential for the maintenance of synaptic circuits in the spinal cord. Thus, the focus of our proposal is: 1) to determine how Nkx6.1 maintains morphology and physiology of ventral spinal cord astrocytes; 2) to delineate how Nkx6.1-dependent astrocyte functions contribute to the activity of spinal cord motor neurons and motor behaviors, and 3) to define the unique transcriptional mechanism controlled by Nkx6.1 in ventral spinal cord astrocytes.