This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pagliardini, S. Articles by Greer, J. J. Search for Related Content PubMed PubMed Citation Articles by Pagliardini, S. Articles by Greer, J. J.

(American Journal of Pathology. 2005;167:175-191.)
© 2005 American Society for Investigative Pathology

Developmental Abnormalities of Neuronal Structure and Function in Prenatal Mice Lacking the Prader-Willi Syndrome Gene Necdin

Silvia Pagliardini^*, Jun Ren^*, Rachel Wevrick and John J. Greer^*

From the Department of Physiology,^* Centre for Neuroscience, and the Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada

Necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Ndn^tm2Stw mutant mice die shortly after birth because of abnormal respiratory rhythmogenesis generated by a key medullary nucleus, the pre-Bötzinger complex (preBötC). Here, we address two fundamental issues relevant to its pathogenesis. First, we performed a detailed anatomical study of the developing medulla to determine whether there were defects within the preBötC or synaptic inputs that regulate respiratory rhythmogenesis. Second, in vitro studies determined if the unstable respiratory rhythm in Ndn^tm2Stw mice could be normalized by neuromodulators. Anatomical defects in Ndn^tm2Stw mice included defasciculation and irregular projections of axonal tracts, aberrant neuronal migration, and a major defect in the cytoarchitecture of the cuneate/gracile nuclei, including dystrophic axons. Exogenous application of neuromodulators alleviated the long periods of slow respiratory rhythms and apnea, but some instability of rhythmogenesis persisted. We conclude that deficiencies in the neuromodulatory drive necessary for preBötC function contribute to respiratory dysfunction of Ndn^tm2Stw mice. These abnormalities are part of a more widespread deficit in neuronal migration and the extension, arborization, and fasciculation of axons during early stages of central nervous system development that may account for respiratory, sensory, motor, and behavioral problems associated with PWS.

This article has been cited by other articles:

				C. Gaultier and J Gallego Neural control of breathing: insights from genetic mouse models J Appl Physiol, May 1, 2008; 104(5): 1522 - 1530. [Abstract] [Full Text] [PDF]

				S. Zanella, F. Watrin, S. Mebarek, F. Marly, M. Roussel, C. Gire, G. Diene, M. Tauber, F. Muscatelli, and G. Hilaire Necdin Plays a Role in the Serotonergic Modulation of the Mouse Respiratory Network: Implication for Prader-Willi Syndrome J. Neurosci., February 13, 2008; 28(7): 1745 - 1755. [Abstract] [Full Text] [PDF]

				J. M. Bischof, C. L. Stewart, and R. Wevrick Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome Hum. Mol. Genet., November 15, 2007; 16(22): 2713 - 2719. [Abstract] [Full Text] [PDF]

				D. Deponti, S. Francois, S. Baesso, C. Sciorati, A. Innocenzi, V. Broccoli, F. Muscatelli, R. Meneveri, E. Clementi, G. Cossu, et al. Necdin mediates skeletal muscle regeneration by promoting myoblast survival and differentiation J. Cell Biol., October 22, 2007; 179(2): 305 - 319. [Abstract] [Full Text] [PDF]

				M. Kurita, T. Kuwajima, I. Nishimura, and K. Yoshikawa Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis. J. Neurosci., November 15, 2006; 26(46): 12003 - 12013. [Abstract] [Full Text] [PDF]

				J. J. Greer, G. D. Funk, and K. Ballanyi Preparing for the first breath: prenatal maturation of respiratory neural control J. Physiol., February 1, 2006; 570(3): 437 - 444. [Abstract] [Full Text] [PDF]