BMP control of preganglionic neuron development

描述(申请人提供)：本提案的主要目的是阐明在发育中的脊髓中控制交感节前神经元分化的分子事件。SPN是脊髓内脏运动神经元，在回路中支配周围交感神经节，介导自主神经应激反应。鸡和小鼠脊髓中的有丝分裂后SPN前体被一种识别活性骨形态发生蛋白(BMP)信号的抗体标记，在缺乏BMP受体活性的条件性小鼠模型中，SPN的正常发育被扰乱。这些观察结果表明，这个信号对SPN命运的指定是有指导意义的，或者是执行SPN发育程序所必需的。因此，这项建议将集中在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SPN的已知标记、脊髓中特定的细胞谱系和接受BMP信号的细胞群之间的关系。其次，将在小鼠和小鸡的突变体中检查SPN和脊髓中其他神经元群体在有丝分裂后分化中对BMP信号的需求。第三，SPN前体在条件性小鼠模型中的命运将被确定。第四，我们将研究限制通常广泛的BMP信号传递到SPN谱系的机制。特别是，将在鸡脊髓中评估异位激活的BMP信号通路组件对躯体运动神经元发育的影响。 总之，这些研究旨在确定导致SPN有丝分裂后分化的分子途径，并限制这种离散细胞群的BMP信号活性。这些研究将促进我们对脊髓发育的一般理解，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有效运作所必需的。在脊髓损伤或包括帕金森氏症在内的神经退行性疾病中，它们可能会被破坏。因此，定义控制SPN发展的分子步骤可能会提供对这些疾病的基础的洞察，并导致治疗这些疾病的新策略。

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.