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在发育中的脊髓中控制交感神经节前神经元（spn）分化的分子事件。spn是脊髓内脏运动神经元，在神经回路中支配周围交感神经节，介导自主应激反应。鸡和小鼠脊髓中有丝分裂后的SPN前体被一种抗体标记，该抗体识别活跃的骨形态发生蛋白（BMP）信号，在缺乏BMP受体活性的条件小鼠模型中，正常的SPN发育被破坏。这些观察结果表明，该信号要么对SPN的命运规范具有指导意义，要么是SPN发展计划的执行所必需的。因此，本提案将重点关注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spn标记物、脊髓中特定细胞系和接收BMP信号的细胞群之间的关系。其次，将在小鼠和鸡突变体中研究脊髓spn和其他神经元群有丝分裂后分化对BMP信号的需求。第三，确定条件小鼠模型中SPN前体的命运。第四，将研究限制通常广泛的BMP信号传导到SPN谱系的机制。特别地，将在小鸡脊髓中评估外位激活BMP信号通路组分对体细胞运动神经元发育的影响。

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.