Absence of Ndn, encoding the Prader-Willi syndrome-deleted gene necdin, results in congenital deficiency of central respiratory drive in neonatal mice.
necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome. necdin is upregulated during neuronal differentiation and is thought to play a role in cell cycle arrest in terminally differentiated neurons. Most necdin-deficient Ndn(tm2Stw) mutant pups carrying a targeted replacement of Ndn with a lacZ reporter gene die in the neonatal period of apparent respiratory insufficiency. We now demonstrate that the defect can be explained by abnormal neuronal activity within the putative respiratory rhythm-generating center, the pre-Bötzinger complex. Specifically, the rhythm is unstable with prolonged periods of depression of respiratory rhythmogenesis. These observations suggest that the developing respiratory center is particularly sensitive to loss of necdin activity and may reflect abnormalities of respiratory rhythm-generating neurons or conditioning neuromodulatory drive. We propose that necdin deficiency may contribute to observed respiratory abnormalities in individuals with Prader-Willi syndrome through a similar suppression of central respiratory drive.
Ren
Jun
J
Centre for Neuroscience, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2M7.
Lee
Syann
S
Pagliardini
Silvia
S
Gérard
Matthieu
M
Stewart
Colin L
CL
Greer
John J
JJ
Wevrick
Rachel
R
D000818:Animals; D000831:Animals, Newborn; D001683:Biological Clocks / Q000235:genetics; D001933:Brain Stem / Q000473:pathology / Q000503:physiopathology; D003964:Diaphragm / Q000503:physiopathology; D004576:Electromyography; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D018408:Patch-Clamp Techniques; D011218:Prader-Willi Syndrome / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D012125:Respiratory Center / Q000196:embryology / Q000473:pathology / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000151:congenital* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C069766:necdin