Molecular Mechanisms of Respiratory Circuit Connectivity

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PROJECT SUMMARY/ABSTRACT Breathing is an essential motor function for terrestrial life. Developmental and genetic disorders that disrupt breathing, such as sudden infant death syndrome (SIDS) and Rett syndrome, often have fatal consequences. This is likely due to the impaired development of neural circuits that control breathing. While diaphragm muscle contractions, the driving force for inspiration in mammals, are controlled solely by motor neurons (MNs) located in the phrenic motor column (PMC), respiration is regulated by complex neural circuitry in the hindbrain. Despite the critical importance of these circuits, the molecular mechanisms that underlie their connectivity are largely unknown. Our lab has shown that Hox5 transcription factors (TFs) drive phrenic MN connectivity and regulate the expression of phrenic-specific cell adhesion molecules. My preliminary data indicate that Hox5 expression varies across hindbrain respiratory nuclei, perhaps acting to confer subtype-specific characteristics required for connectivity. In this proposal, I will investigate the function of Hox5 TFs and their downstream effectors in establishing respiratory circuit connectivity. In Aim 1, I will assess how Hox5 gene expression in respiratory premotor neurons underlies specific connectivity between respiratory populations required for proper circuit function. In Aim 2, I will use genetic manipulations to determine how select cell adhesion molecules act downstream of Hox5 TFs to control respiratory connectivity and function. I have developed an integrative methodology combining genetic models, RNA-sequencing, retrograde viral tracing, and electrophysiology to address these questions. Understanding the molecular mechanisms that underlie respiratory circuit development could lead to improved treatment options for those suffering from developmental or genetic diseases that affect breathing.