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The Journal of Neuroscience, October 22, 2008, 28(43):11030-11041; doi:10.1523/JNEUROSCI.1648-08.2008

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Development/Plasticity/Repair
Central Respiratory Rhythmogenesis Is Abnormal in Lbx1- Deficient Mice

Silvia Pagliardini,^1 * Jun Ren,^1 * Paul A. Gray,² Cassandra VanDunk,² Michael Gross,³ Martyn Goulding,³ and John J. Greer¹

¹Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2S2, ²Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, Missouri, 63110-1093, and ³Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037

Correspondence should be addressed to John J. Greer at the above address. Email: John.Greer{at}ualberta.ca

Lbx1 is a transcription factor that determines neuronal cell fate and identity in the developing medulla and spinal cord. Newborn Lbx1 mutant mice die of respiratory distress during the early postnatal period. Using in vitro brainstem–spinal cord preparations we tested the hypothesis that Lbx1 is necessary for the inception, development and modulation of central respiratory rhythmogenesis. The inception of respiratory rhythmogenesis at embryonic day 15 (E15) was not perturbed in Lbx1 mutant mice. However, the typical age-dependent increase in respiratory frequency observed in wild-type from E15 to P0 was not observed in Lbx1 mutant mice. The slow respiratory rhythms in E18.5 Lbx1 mutant 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 in Lbx1 mutant 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.

Key words: preBötzinger complex; transcription factor; apnea; medulla; fetal; Bötzinger

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Received April 15, 2008; revised Sept. 12, 2008; accepted Sept. 15, 2008.

Correspondence should be addressed to John J. Greer at the above address. Email: John.Greer{at}ualberta.ca

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