BMP control of preganglionic neuron development

描述（由申请人提供）：本提案的主要目标是阐明控制发育中脊髓中交感节前神经元（SPN）分化的分子事件。SPNs是脊髓内脏运动神经元，其在回路中支配外周交感神经节以介导自主应激反应。鸡和小鼠脊髓中的有丝分裂后SPN前体用识别活性骨形态发生蛋白（BMP）信号传导的抗体标记，并且在缺乏BMP受体活性的条件小鼠模型中正常SPN发育被破坏。这些观察结果表明，该信号是指导性的SPN命运规格，或需要执行的SPN发展计划。因此，该建议将集中在SPN分化的四个方面及其与BMP信号通路的关系。首先，将在转基因小鼠中确定已知的SPN标记物、脊髓中的特定细胞谱系和接收BMP信号的细胞群之间的关系。第二，将在小鼠和鸡突变体中检查SPN和脊髓中其他神经元群体的有丝分裂后分化对BMP信号传导的需求。第三，将确定条件性小鼠模型中SPN前体的命运。第四，将检查限制通常广泛的BMP信号传导到SPN谱系的机制。特别地，将在鸡脊髓中评估异位激活BMP信号传导通路组分对体运动神经元发育的后果。 总之，这些研究旨在确定负责SPN有丝分裂后分化和限制BMP信号传导活性的分子途径。这些研究将促进我们对脊髓发育的全面了解，并为关键的发育信号通路提供重要的见解。SPN和交感神经节之间的神经元回路是许多器官系统的有效功能所必需的。它们可以在脊髓损伤或神经退行性疾病（包括帕金森病）中被破坏。因此，确定控制SPN发展的分子步骤可能会深入了解这些疾病的基础，并导致其治疗的新策略。

DESCRIPTION (provided by applicant): The major goal of this proposal is to clarify the molecular events that control the differentiation of sympathetic preganglionic neurons (SPNs) in the developing spinal cord. SPNs are spinal cord visceral motor neurons that innervate the peripheral sympathetic ganglia in circuits to mediate autonomic stress responses. Postmitotic SPN precursors in chick and mouse spinal cords are labeled with an antibody that recognizes active bone morphogenetic protein (BMP) signaling, and normal SPN development is disrupted in a conditional mouse model lacking BMP receptor activity. These observations suggest that this signal is either instructive for SPN fate specification, or required for the execution of the SPN developmental program. This proposal will therefore focus on four aspects of SPN differentiation and its relationship to the BMP signaling pathway. First, the relationship between known markers of SPNs, specific cell lineages in the spinal cord, and the cell population receiving the BMP signal will be defined in transgenic mice. Second, the requirement for BMP signaling in postmitotic differentiation of SPNs and other neuronal populations in the spinal cord will be examined in mouse and chick mutants. Third, the fate of SPN precursors in the conditional mouse model will be determined. Fourth, the mechanism that restricts the usually broad range of BMP signaling to the SPN lineage will be examined. In particular, the consequences to somatic motor neuron development of ectopically-activating BMP signaling pathway components will be assessed in the chick spinal cord. Together, these studies are intended to define the molecular pathway responsible for the postmitotic differentiation of SPNs and for limiting BMP signaling activity to this discrete cell population. These studies will advance our general understanding of spinal cord development, and provide important insight into a critical developmental signaling pathway. Neuronal circuits between SPNs and sympathetic ganglia are required for the efficient function of many organ systems. They can be disrupted following spinal cord injury or in neurodegenerative diseases, including Parkinson's disease. Defining the molecular steps that control SPN development may therefore provide insight into the basis of these disorders and lead to novel strategies for their treatment.