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 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.
Kuwako
Ken-ichiro
K
Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
Hosokawa
Akari
A
Nishimura
Isao
I
Uetsuki
Taichi
T
Yamada
Masashi
M
Nada
Shigeyuki
S
Okada
Masato
M
Yoshikawa
Kazuaki
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005220:Fathers; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D015870:Gene Expression; D018392:Genomic Imprinting / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009475:Neurons, Afferent / Q000166:cytology* / Q000502:physiology; D009619:Nociceptors / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016716:PC12 Cells; D011218:Prader-Willi Syndrome / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020800:Receptor, Nerve Growth Factor; C069766:necdin; D020917:Receptor, trkA