Phox2b, Congenital Central Hypoventilation Syndrome and the Control of Respiration

Neural networks in the hindbrain generate the pattern of motor activity that sustains breathing in mammals. Over the last years, increasing knowledge of the development and the molecular signatures of different classes of hindbrain neurons has led to a better definition of the neuronal circuits essential for adequate breathing. Here, we review how, on the basis of earlier clinical and genetic studies of a human respiratory disease, evidence from neurophysiology and mouse genetics has led to the conclusion that a restricted number of neuronal types expressing and depending on the Phox2b transcription factor play crucial roles in the control of respiration. Collectively, these studies argue for the paramount importance of a small group of neurons in the rostral medulla termed the retrotrapezoid nucleus (RTN) both for the vital drive to breathe afforded by CO(2) detection in the brain and for the pacing of respiratory rhythm before birth. RTN neurons are now among the molecularly and developmentally best defined types of respiratory neurons. Such knowledge will enable new genetic approaches towards elucidating how respiratory networks are assembled and configured in normal and pathological conditions.