Pre-patterning of Skeletal Muscle

描述（来自申请人的摘要）：突触形成的当前想法 这表明肌肉是由运动提供信号（如聚集蛋白）形成的 神经元然而，我们最近的研究表明，肌肉是 在缺乏神经支配的情况下预先形成图案。我们发现大脑顶部的运动轴突 2b突变体胚胎达到它们的目标，但不能在肢内生长或分支， 横隔膜肌令我们惊讶的是，我们发现乙酰胆碱受体聚集在 肌肉的中央区域，尽管肌肉内没有运动轴突。 这些结果表明，骨骼肌AChRs的表达模式 至少部分是由肌肉的自主机制决定的 并表明肌肉是预先形成的，不依赖于 运动神经元本提案中描述的实验旨在 确定肌肉的预模式是如何建立的， 前模式可能调节轴突终止和形成突触的位置， 神经支配可能调节肌肉的预模式化。我们将确定（1）是否 运动神经支配需要top 2b的神经或肌肉表达，（2）是否 需要来自运动轴突的信号来预形成骨骼肌中的AChR， (3)是否需要MuSK或聚集蛋白来建立肌肉预模式，（4） 额外的骨骼肌蛋白是否在肌肉中预先形成图案，（5） 编码突触蛋白的基因是否在肌肉中预先形成模式，（6） 预先形成图案的分子是否可能在指定 运动神经支配，（7）运动轴突或电活动是否抑制 肌肉预图案化，以及（8）是否一个独特的成肌细胞谱系可能是一个 前模式的来源。

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.