AMPK Phosphorylates LMX1b to Regulate a Brainstem Neurogenic Network Important for Control of Breathing in Neonatal Mice

Ventilatory drive is modulated by a variety of neurochemical inputs that converge on spatially oriented clusters of cells within the brainstem. This regulation is required to maintain energy homeostasis and is essential to sustain life across all mammalian organisms. Therefore, the anatomical orientation of these cellular clusters during development must have a defined mechanistic basis with redundant genomic variants. Failure to completely develop these features causes several conditions including apnea of prematurity (AOP) and sudden infant death syndrome (SIDS). AOP is associated with many adverse outcomes including increased risk of interventricular hemorrhage. However, there are no pharmacological interventions that reduce SIDS and AOP prevalence by promoting brainstem development. AMP-activated protein kinase (AMPK) is a kinase that regulates ventilatory control to maintain homeostasis. This study identifies a signaling axis in which the pharmacological activation of AMPK in vivo via metformin in brainstem ventilatory control centers results in the phosphorylation of LIM homeobox transcription factor 1-beta (Lmx1b), a key player in dorsal-ventral patterning during fetal development. The phosphorylation of Lmx1b transactivates a neurogenic interactome important for the development and regulation of ventilatory control centers. These findings highlight the potential for metformin in the treatment and prevention of AOP.