Embryonic hindbrain patterning genes delineate distinct cardio-respiratory and metabolic homeostatic populations in the adult

Abstract

Previous studies based on mouse genetic mutations suggest that proper partitioning of the hindbrain into transient, genetically-defined segments called rhombomeres is required for normal respiratory development and function in neonates. Less clear is what role these genes and the neurons they define play in adult respiratory circuit organization. Several Cre drivers are used to access and study developmental rhombomeric domains (Eng1 Cre, HoxA2-Cre, Egr2 Cre, HoxB1 Cre, and HoxA4-Cre) in the adult. However, these drivers show cumulative activity beyond the brainstem while being used in intersectional genetic experiments to map central respiratory circuitry. We crossed these drivers to conditional DREADD mouse lines to further characterize the functional contributions of Cre defined populations. In the adult, we show that acute DREADD inhibition of targeted populations results in a variety of not only respiratory phenotypes but also metabolic and temperature changes that likely play a significant role in the observed respiratory alterations. DREADD mediated excitation of targeted domains all resulted in death, with unique differences in the patterns of cardio-respiratory failure. These data add to a growing body of work aimed at understanding the role of early embryonic patterning genes in organizing adult respiratory homeostatic networks that may be perturbed in congenital pathophysiologies.