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.
Respiratory motor activities begin in fetal development and persist until death. The proposed research seeks to define the molecular pathways underlying the formation of respiratory motor neurons in the spinal cord and assembly of functional motor circuits. Insights into the process will greatly advance our understanding of the basis of neurological disorders that impair respiratory functions, and future efforts to evoke repair of the diseased or damaged spinal cord by harnessing these developmental mechanisms.
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