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

脊髓回路中区域特异性星形胶质细胞功能的转录控制

• 批准号: 10314322
• 负责人: Navish Alejandro Bosquez Huerta
• 金额: $ 4.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-30 至 2025-07-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314322
• 关键词: Adult; Affect; Astrocytes; Ataxia; Behavior; Binding; Blood - brain barrier anatomy; Candidate Disease Gene; Cell Communication; Cells; Cellular Morphology; ChIP-seq; Choline O-Acetyltransferase; Communication; Data; Disease; Electrophysiology (science); Exhibits; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Homeobox; Image; Immunohistochemistry; In Situ Hybridization; Laboratories; Lateral; Maintenance; Measures; Metabolic; Molecular; Morphology; Motor; Motor Neurons; Mus; Neuraxis; Neuroglia; Neurologic; Neurons; Neurotransmitters; Physiological; Physiology; Population; Potassium Channel; Process; Property; Recycling; Reporter; Resolution; Role; Semaphorin-3A; Signal Transduction; Slice; Spinal; Spinal Cord; Synapses; Testing; Transcriptional Regulation; United States; Viral; base; behavior test; conditional knockout; dexterity; genetic manipulation; motor behavior; motor control; motor disorder; nervous system development; nervous system disorder; neural circuit; neuron loss; neuronal circuitry; novel; response; synaptogenesis; transcription factor; two-photon; virtual

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.

项目概要 星形胶质细胞对于中枢神经元回路的生成、维持和功能至关重要 神经系统（CNS）。我们实验室的最新研究表明，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。要了解这个功能如何 多样性被编码后，我们鉴定了几种表现出区域特异性表达的转录因子（TF）。 尽管有这些发现，转录因子如何促进星形胶质细胞生理学和回路功能仍然在很大程度上 不明确的。在表现出区域特异性表达的 TF 中，我们发现同源盒 TF Nkx6.1 是 仅在成熟脊髓的腹侧星形胶质细胞中表达。 Nkx6.1 的时间条件删除 来自成熟星形胶质细胞 (Nkx6.1-cKO) 导致腹侧星形胶质细胞形态复杂性较低 脊髓表明它调节这些星形胶质细胞群的关键特性。另外，电机 Nkx6.1-cKO 脊髓神经元表现出胆碱乙酰转移酶表达减少 伴随着 VGlut1 突触数量的减少。最后，ChIP-seq 分析显示 Nkx6.1 结合， 并可能调节参与细胞形态、神经元-星形胶质细胞通讯的基因的表达， 和突触维护。总之，这些结果表明 Nkx6.1 维持成熟的星形胶质细胞功能 这对于维持脊髓突触回路至关重要。因此，我们建议的重点是： 1) 确定Nkx6.1如何维持腹侧脊髓星形胶质细胞的形态和生理学； 2）到 描述 Nkx6.1 依赖性星形胶质细胞功能如何促进脊髓运动神经元的活动和 运动行为，3) 定义腹侧脊髓中 Nkx6.1 控制的独特转录机制 脐带星形胶质细胞。