期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 167, 期 1, 页码 175-191出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)62964-1
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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-Botzinger complex (preBotC). 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 preBotC or synaptic inputs that regulate respiratory rhythmogenesis. Second, in vitro studies determined if the unstable respiratory rhythm in Ndns(tm2Stw) mice could be normalized by neuro-modulators. 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 preBotC 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.
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