Pattern Formation in the Sympathetic Nervous System

描述(申请人提供)：交感节前神经元既表现为节段内模式，即投射到交感神经链上的细胞位于节段的吻端，而投射到交感神经链的尾端的细胞位于节段的尾部，也表现为节段间的模式，即脊髓节段内吻端或尾端投射的细胞的数量由脊椎节段沿肩尾轴的节段位置决定。证据表明，节前细胞根据它们投射到交感神经链的模式，分为两个不同的群体。首先，单个细胞在吻部或尾部投射到交感神经链中，但很少是双向的。其次，对旁中胚层的操作，如在发育中的体节上应用外源性维甲酸或成纤维细胞生长因子，或将体节沿吻尾轴移位，都会不同地改变节前细胞池。这些研究表明，胸髓节前细胞柱的投射模式在发育早期受到外周线索的影响。我们假设节前神经元具有作为吻侧或尾侧投射细胞的固有身份，并且这种身份是在早期发育中由调节模式形成的基因指定的。这项应用的具体目的是为了阐明交感节前细胞柱中指定神经元身份的机制。前三个目标将决定调控这个系统中的模式的信号信号可能会在何时何地起作用。后两个目的将检验特定的假设，即在交感节前细胞柱的投射模式中指定节间梯度的位置信息由HOX基因和控制HOX表达的基因调节。具体目标是：具体目标：1.确定体节手法对节前细胞柱模式影响的时间界限。具体目的2.验证吻侧投射节前神经元先于尾侧投射节前神经元的假说。具体目的3.验证节前神经元轴突离开脊髓时相对于躯体运动神经元有时间延迟的假说。具体目的4.验证特定节前细胞类型沿胸髓纵轴的分布是由HOX编码决定的假说。具体目的5.检验节前细胞柱模式的HOX密码规范受Polycomb/Trithorax组调控蛋白成员调控的假设。

DESCRIPTION (provided by applicant): Sympathetic preganglionic neurons exhibit both an intrasegmental pattern, in which cells destined to project rostrally into the sympathetic chain are located rostrally in the segment, while those that project caudally into the sympathetic chain are located caudally in the segment, and an intersegmental pattern, in which the number of rostrally or caudally projecting cells within a spinal segment is determined by the segmental position along the rostrocaudal axis. Evidence suggests that preganglionic cells comprise two distinct groups, based on their pattern of projection into the sympathetic chain. First, individual cells project either rostrally or caudally into the sympathetic chain, but rarely in both directions. Second, manipulations of the paraxial mesoderm, such as application of exogenous retinoic acid or fibroblast growth factor to the developing somites, or transposition of somites along the rostrocaudal axis, differentially alter the preganglionic cell pools. These studies demonstrate that the pattern of projections from the preganglionic cell column in the thoracic spinal cord is influenced by peripheral cues early in development. We hypothesize that preganglionic neurons have an inherent identity as either rostrally or caudally projecting cells and that this identity is specified in early development by genes that regulate pattern formation. The specific aims of this application are designed to elucidate the mechanisms that specify neuronal identity in the sympathetic preganglionic cell column. The first three aims will determine when and where signaling cues that regulate pattern in this system might act. The last two aims will test the specific hypothesis that the positional information that specifies the intersegmental gradient in the pattern of projections from the sympathetic preganglionic cell column is regulated by Hox genes and the genes that control Hox expression. The specific aims are: Specific Aim 1.To determine the temporal limits of the effect of somite manipulations on pattern in the preganglionic cell column. Specific Aim 2. To test the hypothesis that rostrally projecting preganglionic neurons are born before caudally projecting preganglionic neurons. Specific Aim 3. To test the hypothesis that preganglionic neuronal axons exit the spinal cord with a temporal delay relative to somatic motor neurons. Specific Aim 4. To test the hypothesis that the distribution of specific preganglionic cell types along the longitudinal axis of the thoracic spinal cord is determined by the Hox code. Specific Aim 5. To test the hypothesis that Hox code specification of pattern in the preganglionic cell column is regulated by members of the Polycomb/Trithorax group of regulatory proteins.