Molecular and Functional Characterization of the Developing Respiratory Motor Circuit
The faithful and sophisticated control of motor neurons (MNs) allows for our ability to walk, chew, breathe, and speak. This dissertation is focused on the characterization of MNs and the intricate circuitry that are involved in the control of these MNs that surround the airways. The relevance of this study goes beyond satisfying our curiosity of the physiology of breathing. This knowledge is critical in their application in respiratory medicine and speech rehabilitation – as the same set of MNs generate rudimentary vocal sounds in rodents and may provide us with a greater understanding about speech motor pathways in humans.
The dissertation begins with a literature review of principles of circuit assembly predominantly centered in the spinal cord. In Chapter 2, I define the molecular organization of the cranial MNs in the brainstem. Unique transcription factors and guidance cues including Foxp1, Pou3f1, Etv4, and Npn2 label specific cranial motor pools that match previously described motor populations identified by classic retrograde labeling. This molecular definition of cranial motor pools opens up new doors for us to understand their origins to harness the potential for rehabilitation when these MNs are diseased or injured.
In Chapter 3, I demonstrate that the respiratory drive can extend to brachial limb-innervating MNs, a feature normally suppressed by Foxp1. In the absence of Foxp1, the limb-innervating MNs exhibit molecular and anatomical characteristics that resemble that of the thoracic respiratory MNs. The findings of this study provide another compelling evidence that the respiratory motor circuit can integrate MNs out of their usual field of innervation to harbor ectopic respiratory MNs – similar to the respiratory drive crossing the midline in the crossed phrenic phenomenon.
In Chapter 4, through genetic manipulation I show that Pou3f1, a marker for phrenic and other respiratory MN populations, is essential for proper the phrenic nerve branch projection and intercostal cell fate specification. Finally in Chapter 5, I summarize the key findings of my dissertation and discuss the limitations as well as remaining questions. Together, the results presented in my dissertation have a significant impact on our understanding of the respiratory motor pathways, which could be applied for the regeneration of diseased cells or rehabilitation efforts to accelerate the recovery of motor circuitry involved in breathing, speech, and language.