Molecular Pathways Controlling Respiratory Motor Neuron Formation and Function

 描述（由申请人提供）：呼吸是我们最重要的运动活动，从出生开始，一直持续到死亡。脊髓中的呼吸运动神经元（MN）是这种重要功能的核心，其神经支配不同的肌肉目标，例如隔膜、肋间肌和腹肌，以产生交替的吸气和呼气运动。这些活动主要是由脑干中节律产生神经元提供的下行输入驱动的，这些神经元选择性地与呼吸MN形成单突触突触，同时避免其他MN类。呼吸运动回路形成的缺陷可导致从睡眠呼吸暂停到潜在致命的呼吸窘迫综合征的各种呼吸障碍。此外，呼吸运动丧失或功能障碍是许多神经退行性疾病和创伤性损伤中死亡的主要原因。尽管呼吸MN功能对生存的重要性，但对这些细胞的发育起源以及引导其组装成功能性运动回路的机制知之甚少。在我们以前的工作中，我们确定了一个新的人口的脊髓MN称为hypaxial运动柱（HMC）与神经支配的体壁肌肉和隔膜。我们进一步发现HMC MN的形成受到转录因子Foxp1的积极抑制。在Foxp1突变体中，MN获得HMC特征，并显示出对呼吸肌靶的旺盛生长。根据这些发现，我们首先得出结论，呼吸MN可能是HMC的成熟衍生物，其次Foxp1在抑制呼吸MN形成过程中起着关键作用。我们建立在这些观察，以阐明通过呼吸运动回路构建的发展计划。在目标1中，我们将研究HMC的组织特征，特别是其与吸气和呼气运动活动相关的池的细分。我们还将研究转录因子的功能，我们的初步研究表明，吸气和呼气的MN亚群，从而传达这些MN活动的候选人的表达。最后，在目标2中，我们将研究如何下降呼吸运动前输入从脑干响应的变化，无论是不同MN亚型的分子身份或其在脊髓内的轴突靶向和选择突触伴侣的定居位置。通过这些研究，我们希望获得基本的见解呼吸运动回路是如何构建和中枢神经系统下行通路的组织原则。这些信息对于理解损害呼吸功能的疾病的基础，以及未来通过利用这些发育机制来修复患病或受损的脊髓的努力将是非常宝贵的。

 DESCRIPTION (provided by applicant): Breathing is the most essential of our motor activities that starts at birth and persists until death. At the core of this vital function are respiratory mtor neurons (MNs) in the spinal cord that innervate distinct muscle targets such as the diaphragm, intercostals, and abdominals to produce alternating inspiratory and expiratory movements. These activities are principally driven by descending inputs provided by rhythm generating neurons in the brainstem that selectively form monosynaptic synapses with respiratory MNs while avoiding other MN classes. Defects in respiratory motor circuit formation can result in a variety of breathing disorders ranging from sleep apneas to potentially fatal respiratory distress syndromes. Moreover, respiratory motor loss or dysfunction is the primary cause of death in many neurodegenerative diseases and traumatic injuries. Despite the importance of respiratory MNs function for survival, remarkably little is known about the developmental origins of these cells and the mechanisms that guide their assembly into functional motor circuits. In our previous work, we identified a novel population of spinal MNs termed the hypaxial motor column (HMC) associated with innervation of body wall muscles and the diaphragm. We further discovered that HMC MN formation is actively suppressed by the transcription factor Foxp1. In Foxp1 mutants, MNs acquire HMC characteristics and display exuberant growth towards respiratory muscle targets. From these findings we conclude first that respiratory MNs are likely the mature derivatives of the HMC, and second that Foxp1 plays a critical role suppressing the program of respiratory MN formation. We build upon these observations to elucidate the developmental program through which respiratory motor circuits are constructed. In Aim 1, we will examine the organizational features of the HMC, particularly its subdivision into pools associated with inspiratory and expiratory motor activities. We will also examine the function of transcription factors that our preliminary studies show are reciprocally expressed by inspiratory and expiratory MN subpopulations and thus candidates for conveying these MN activities. Lastly, in Aim 2, we will examine how descending respiratory premotor inputs from the brainstem respond to changes in either the molecular identity of different MN subtypes or their settling position within the spinal cord in terms of axonal targeting and selection of synaptic partners. Through these studies we hope to gain fundamental insights into how respiratory motor circuits are constructed and the organizational principles of descending pathways in the CNS. This information will be invaluable for understanding the basis of disorders that impair respiratory functions, and future efforts to evoke repair of the diseased or damaged spinal cord by harnessing these developmental mechanisms.