Developmental Abnormalities of Neuronal Structure and Function in Prenatal Mice Lacking the Prader-Willi Syndrome Gene Necdin
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Necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Ndntm2Stw 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 Ndntm2Stw mice could be normalized by neuromodulators. Anatomical defects in Ndntm2Stw 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 Ndntm2Stw 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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Necdin-deficient mice have small brainstem nuclei and disorganized axonal tracts in the medulla.
“Necdin-deficient mice have small brainstem nuclei and disorganized axonal tracts in the medulla [271].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [271]
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- Authors
- Pagliardini, S., Ren, J., Wevrick, R., & Greer, J. J.
- Affiliations
- University of Alberta (CA)
- Corresponding author
- Greer, John J.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 167
- Issue
- 1
- Pages
- 175-191
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1603432
- OpenAlex
- W2024673645
- Cited by
- 99
- References
- 92
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 2 · 2017: 4 · 2016: 6 · 2014: 5 · 2013: 5 · 2012: 10
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Prader-Willi syndrome, NDN, pre-Bötzinger complex, respiratory rhythmogenesis, medulla oblongata, neuronal migration, axonal fasciculation, cuneate nucleus, gracile nucleus, neuromodulators, apnea, developmental abnormalities
- MeSH terms
- Animals, Diaphragm, Disease Models, Animal, Female, Fetus, Immunohistochemistry, Mice, Neurologic Mutants, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Organ Culture Techniques, Prader-Willi Syndrome, Pregnancy, Respiratory Center, Spinal Cord, Microscopy, Confocal, Mice
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