Generation of neuronal diversity by temporal mechanisms in the developing spinal cord

发育中的脊髓通过时间机制产生神经元多样性

• 批准号: 455354162
• 负责人: Dr. Andreas Sagner
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455354162?language=en
• 关键词: Generation; neuronal; diversity; temporal; mechanisms

In the vertebrate spinal cord different classes of neurons form the neuronal circuits that allow us to move and perceive our environment. During development, these distinct classes of neurons are generated in response to spatial cues that pattern the embryonic neural tube along its dorsal-ventral axis. This subdivision however is not sufficient to account for the complexity of neurons observed in the spinal cord - instead each neuronal class can be further divided into distinct subtypes based on molecular and functional characteristics. The signals and gene regulatory networks that orchestrate the specification of these neuronal subtypes and underlie their correct incorporation into circuits with specific functions are still largely unclear.My recent work uncovered a temporal dimension to neuronal subtype specification in the spinal cord, which depends on cohorts of transcription factors (TFs) that are specific for early, intermediate, or late-born neurons. Here, I propose that this temporal TF program is essential and works in combination with the spatial TFs that define the identity of the distinct neuronal classes to establish neuronal diversity and the correct patterns of neuronal connectivity in the spinal cord. To test this hypothesis, I plan to combine in vitro stem cell differentiation with genomic assays, in vivo genetic tracing and functional perturbation approaches. The key aims of this proposal are to:1. Characterize the signals and gene regulatory networks orchestrating the temporal stratification of neurons in the spinal cord,2. Investigate the molecular logic by which spatial and temporal TFs jointly establish neuronal subtype-specific patterns of gene Expression, 3. Delineate how temporal TF expression in the embryo underlies neuronal diversity and connectivity in the adult spinal cord. The expected results of my proposal will provide a detailed understanding how spatial and temporal patterning systems jointly specify neuronal diversity and underlie the correct formation of neuronal circuitry in the mouse spinal cord. Ultimately, such mechanistic understanding of cell fate and connectivity will underpin the development of novel disease models and therapies for neurodegenerative movement disorders and spinal injuries.

在脊椎动物的脊髓中，不同种类的神经元形成了神经元回路，使我们能够移动和感知我们的环境。在发育过程中，这些不同类别的神经元是响应空间线索而产生的，这些空间线索使胚胎神经管沿着其背腹轴形成图案。然而，这种细分不足以解释在脊髓中观察到的神经元的复杂性-相反，每个神经元类别可以基于分子和功能特征进一步分为不同的亚型。这些神经元亚型的特化以及它们正确整合到具有特定功能的电路中的信号和基因调控网络仍然很不清楚，我最近的工作揭示了脊髓中神经元亚型特化的时间维度，这取决于对早期，中期或晚期出生的神经元特异性的转录因子（TF）的队列。在这里，我建议，这个时间TF程序是必不可少的，并与空间TF，定义不同的神经元类的身份，以建立神经元的多样性和正确的模式，在脊髓中的神经元连接相结合。为了验证这一假设，我计划将联合收割机体外干细胞分化与基因组测定、体内遗传追踪和功能扰动方法相结合。该提案的主要目的是：1.表征协调脊髓神经元时间分层的信号和基因调节网络，2.研究空间和时间TF共同建立神经元亚型特异性基因表达模式的分子逻辑。描述胚胎中TF的瞬时表达如何成为成年脊髓中神经元多样性和连接性的基础。我的建议的预期结果将提供一个详细的了解空间和时间模式系统如何共同指定神经元的多样性，并在小鼠脊髓神经元回路的正确形成的基础。最终，这种对细胞命运和连接性的机械理解将支持神经退行性运动障碍和脊柱损伤的新型疾病模型和疗法的开发。