Pre-patterning of Skeletal Muscle

描述(摘自申请者的摘要)：突触形成的当前想法 提示肌肉是由马达提供的信号形成的，例如集聚蛋白 神经元。然而，我们最近的研究表明，肌肉是 在没有神经支配的情况下预先形成了图案。我们发现顶端的运动轴突 2B个突变胚胎到达它们的目标，但不能在肢体内生长或分支 横隔肌。令我们惊讶的是，我们发现AChR聚集在 肌肉的中央区域，尽管肌肉内没有运动神经轴突。 这些结果表明，AChRs在骨骼肌中的表达模式 至少部分是由肌肉自主的机制决定的 并表明肌肉是预先构图的，独立于由 运动神经元。本提案中描述的实验旨在 确定肌肉的前模式是如何建立的，肌肉是否 前图案化可能调节轴突在哪里终止和形成突触以及如何 神经支配可能调节肌肉的前置模式。我们将确定(1)是否 运动神经支配需要神经或肌肉表达top 2b，(2)是否 来自运动轴突的信号需要在骨骼肌中预先形成AChR模式， (3)是否需要麝香或集聚蛋白来建立肌肉前图案，(4) 肌肉中是否预先构筑了额外的骨骼肌蛋白质，(5) 编码突触蛋白的基因是否在肌肉中预先形成了模式，(6) 预先图案化的分子是否可能在确定 运动神经支配，(7)运动轴突或电活动是否受到抑制 肌肉前图案化，以及(8)不同的成肌细胞谱系是否可能是 预置模式的来源。

DESCRIPTION (From the Applicant's Abstract): Current ideas of synapse formation suggest that muscle is patterned by signals, such as agrin, provided by motor neurons. Our recent studies, however, have revealed that muscle is pre-patterned in the absence of innervation. We found that motor axons in top 2b mutant embryos reach their targets but fail to grow or branch within limb or diaphragm muscles. To our surprise, we found that AChRs are clustered in the central region of muscle, despite the absence of motor axons within the muscle. These results suggest that the expression pattern of AChRs in skeletal muscles is determined, at least in part, by mechanisms that are autonomous to muscle and suggest that muscle is pre-patterned, independent from signals provided by motor neurons. The experiments described in this proposal are designed to determine how pre-patterning of muscle is established, whether muscle pre-patterning might regulate where axons terminate and form synapses and how innervation might regulate muscle pre-patterning. We will determine (1) whether motor innervation requires neural or muscle expression of top 2b, (2) whether signals from motor axons are required to pre-pattern AChRs in skeletal muscle, (3) whether MuSK or agrin are required to establish muscle pre-patterning, (4) whether additional skeletal muscle proteins are pre-patterned in muscle, (5) whether genes encoding synaptic proteins are pre-patterned in muscle, (6) whether pre-patterned molecules might have a role in specifying the site of motor innervation, (7) whether motor axons or electrical activity suppress muscle pre-patterning, and (8) whether a distinct myoblast lineage might be a source of the pre-pattern.