Disruption of the Paternal Necdin Gene Diminishes TrkA Signaling for Sensory Neuron Survival

Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11-q12 is maternally imprinted, paternally transcribed, and not expressed in Prader-Willi syndrome, a human genomic imprinting-associated neurodevelop...

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Bibliographic Details
Published in:The Journal of neuroscience 2005-07, Vol.25 (30), p.7090-7099
Main Authors: Kuwako, Ken-ichiro, Hosokawa, Akari, Nishimura, Isao, Uetsuki, Taichi, Yamada, Masashi, Nada, Shigeyuki, Okada, Masato, Yoshikawa, Kazuaki
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Cell Survival - physiology
Fathers
Female
Ganglia, Spinal - cytology
Gene Expression
Genomic Imprinting - physiology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurobiology of Disease
Neurons, Afferent - cytology
Neurons, Afferent - physiology
Nociceptors - cytology
Nociceptors - physiology
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
PC12 Cells
Prader-Willi Syndrome - genetics
Pregnancy
Rats
Receptor, Nerve Growth Factor - metabolism
Receptor, trkA - metabolism
Signal Transduction - physiology
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Summary:Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11-q12 is maternally imprinted, paternally transcribed, and not expressed in Prader-Willi syndrome, a human genomic imprinting-associated neurodevelopmental disorder. Although necdin-deficient mice display several abnormal phenotypes reminiscent of this syndrome, little is known about molecular mechanisms that lead to the neurodevelopmental defects. Here, we demonstrate that paternally expressed necdin is required for physiological development of nerve growth factor (NGF)-dependent sensory neurons. Mouse embryos defective in the paternal necdin allele displayed absent necdin expression in the dorsal root ganglia, in which the tropomyosin-related kinase A (TrkA) receptor tyrosine kinase and the p75 neurotrophin receptor were expressed in a normal manner. Necdin interacted with both TrkA and p75 to facilitate the association between these receptors. NGF-induced phosphorylation of TrkA and mitogen-activated protein kinase was significantly diminished in the necdin-null sensory ganglia. Furthermore, the mice lacking the paternal necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P-containing neurons. These mutant mice showed significantly high tolerance to thermal pain, which is often seen in individuals with Prader-Willi syndrome. These results suggest that paternally expressed necdin facilitates TrkA signaling to promote the survival of NGF-dependent nociceptive neurons.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.2083-05.2005