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The Journal of Neuroscience, July 27, 2005, 25(30):7090-7099; doi:10.1523/JNEUROSCI.2083-05.2005

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

Ken-ichiro Kuwako,¹ Akari Hosokawa,¹ Isao Nishimura,¹ Taichi Uetsuki,¹ Masashi Yamada,¹ Shigeyuki Nada,² Masato Okada,² and Kazuaki Yoshikawa¹

¹Institute for Protein Research, and ²Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

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.

Key words: necdin; NGF; apoptosis; sensory neurons; genomic imprinting; Prader-Willi syndrome

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Received May 24, 2005; revised June 20, 2005; accepted June 20, 2005.

This article has been cited by other articles:

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				P. L. Tan and N. Katsanis Thermosensory and mechanosensory perception in human genetic disease Hum. Mol. Genet., October 15, 2009; 18(R2): R146 - R155. [Abstract] [Full Text] [PDF]

				C. Sciorati, T. Touvier, R. Buono, P. Pessina, S. Francois, C. Perrotta, R. Meneveri, E. Clementi, and S. Brunelli Necdin is expressed in cachectic skeletal muscle to protect fibers from tumor-induced wasting J. Cell Sci., April 15, 2009; 122(8): 1119 - 1125. [Abstract] [Full Text] [PDF]

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				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]

				K. Obata, H. Katsura, J. Sakurai, K. Kobayashi, H. Yamanaka, Y. Dai, T. Fukuoka, and K. Noguchi Suppression of the p75 Neurotrophin Receptor in Uninjured Sensory Neurons Reduces Neuropathic Pain after Nerve Injury. J. Neurosci., November 15, 2006; 26(46): 11974 - 11986. [Abstract] [Full Text] [PDF]

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