Central Respiratory Rhythmogenesis Is Abnormal inLbx1- Deficient Mice

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Abstract
Lbx1is a transcription factor that determines neuronal cell fate and identity in the developing medulla and spinal cord. NewbornLbx1mutant mice die of respiratory distress during the early postnatal period. Usingin vitrobrainstem–spinal cord preparations we tested the hypothesis thatLbx1is necessary for the inception, development and modulation of central respiratory rhythmogenesis. The inception of respiratory rhythmogenesis at embryonic day 15 (E15) was not perturbed inLbx1mutant mice. However, the typical age-dependent increase in respiratory frequency observed in wild-type from E15 to P0 was not observed inLbx1mutant mice. The slow respiratory rhythms in E18.5Lbx1mutant preparations were increased to wild-type frequencies by application of substance P, thyrotropin releasing hormone, serotonin, noradrenaline, or the ampakine drug 1-(1,4-benzodioxan-6-yl-carbonyl) piperidine. Those data suggest that respiratory rhythm generation within the pre-Bötzinger complex (preBötC) is presumably functional inLbx1mutant mice with additional neurochemical drive. This was supported by anatomical data showing that the gross structure of the preBötC was normal, although there were major defects in neuronal populations that provide important modulatory drive to the preBötC including the retrotrapezoid nucleus, catecholaminergic brainstem nuclei, nucleus of the solitary tract, and populations of inhibitory neurons in the ventrolateral and dorsomedial medullary nuclei. Finally, we determined that those defects were caused by abnormalities of neuronal specification early in development or subsequent neuronal migration.