Abstract
Nerve regeneration is a complex process associated with the expression of hundreds of genes. To elucidate the molecular mechanism responsible for nerve regeneration, hundreds of nerve regeneration-associated genes have been hunted using differential display polymerase chain reaction (DD-PCR), random cloning, microarray and proteomics. Damage-induced neuronal endopeptidase (DINE) is a newly identified nerve regeneration-related molecule derived from normal and axotomized hypoglosssal nuclei using DD-PCR. After full-length cloning, we have found that DINE is a neuron-specific membrane-bound metalloprotease. Damage-induced neuronal endopeptidase shares homology with neprilysin and endothelin-converting enzyme, which degrade or process neuropeptides. Although DINE has some neuroprotective effects, the physiological function of, as well as the substrate for, DINE remains obscure. The most intriguing property of DINE is its extreme transcriptional response against various types of nerve injuries, including that of the peripheral and central nervous systems. Thus, a more detailed expression profile of DINE mRNA was investigated using the dorsal root ganglion (DRG) after sciatic nerve injury. In the DRG, DINE mRNA was observed in small-sized DRG neurons after axotomy. This expression profile was similar to that of the neuropeptide galanin. Both in vitro and in vivo studies revealed that leukemia inhibitory factor and nerve growth factor withdrawal additively enhanced the expression of DINE, as well as that of galanin. Damage-induced neuronal endopeptidase and galanin may use common transcriptional regulation machinery. Although functional correlation of these molecules remains unclear, their simultaneous induction may provide more successful protection for injured neurons.
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References
Benoit A, Vargas MA, Desgroseillers L, Boileau G (2004) Endothelin-converting enzyme-like 1 (ECEL1) is present both in the plasma membrane and in the endoplasmic reticulum. Biochem J 380, 881–8.
Bradbury EJ, McMahon SB, Ramer MS (2000) Keeping in touch: Sensory neurone regeneration in the CNS. Trends Pharmacol Sci 21, 389–94.
Carson JA, Turner AJ (2002) Beta-amyloid catabolism: Roles for neprilysin (NEP) and other metallopeptidases? J Neurochem 81, 1–8.
Corness J, Stevens B, Fields RD, Hokfelt T (1998) NGF and LIF both regulate galanin gene expression in primary DRG cultures. Neuroreport 9, 1533–6.
Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3, E255–63.
Hokfelt T, Zhang X, Wiesenfeld-Hallin Z (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 17, 22–30.
Holmes FE, Mahoney S, King VR et al. (2000) Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity. Proc Natl Acad Sci USA 97, 11563–8.
Holmes FE, Bacon A, Pope RJ et al. (2003) Transgenic overex- pression of galanin in the dorsal root ganglia modulates pain-related behavior. Proc Natl Acad Sci USA 100, 6180–5.
Kato R, Kiryu-Seo S, Kiyama H (2002) Damage-induced neuronal endopeptidase (DINE/ECEL) expression is regulated by leukemia inhibitory factor and deprivation of nerve growth factor in rat sensory ganglia after nerve injury. J Neurosci 22, 9410–18.
Kiryu S, Yao GL, Morita N, Kato H, Kiyama H (1995) Nerve injury enhances rat neuronal glutamate transporter expression: Identification by differential display PCR. J Neurosci 15, 7872–8.
Kiryu-Seo S, Sasaki M, Yokohama H et al. (2000) Damage- induced neuronal endopeptidase (DINE) is a unique metal- lopeptidase expressed in response to neuronal damage and activates superoxide scavengers. Proc Natl Acad Sci USA 97, 4345–50.
Liang P, Pardee AB (1992) Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257, 967–71.
MacLeod KJ, Fuller RS, Scholten JD, Ahn K (2001) Conserved cysteine and tryptophan residues of the endothelin-converting enzyme-1 CXAW motif are critical for protein maturation and enzyme activity. J Biol Chem 276, 30608–14.
Morita N, Kiryu S, Kiyama H (1996) p53-independent cyclin G expression in a group of mature neurons and its enhanced expression during nerve regeneration. J Neurosci 16, 5961–6.
Nakagomi S, Suzuki Y, Namikawa K, Kiryu-Seo S, Kiyama H (2003) Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J Neurosci 23, 5187–96.
Ohba N, Kiryu-Seo S, Maeda M, Muraoka M, Ishii M, Kiyama H (2004) Expression of damage-induced neuronal endopeptidase (DINE) mRNA in peri-infarct cortical and thalamic neurons following middle cerebral artery occlusion. J Neurochem 91, 956–64.
Ramer MS, Thompson SW, McMahon SB (1999) Causes and consequences of sympathetic basket formation in dorsal root ganglia. Pain (Suppl. 6), S111–20.
Savitz SI, Kessler JA (2000) Leukemia inhibitory factor requires concurrent p75LNTR signaling to induce apoptosis of cultured sympathetic neurons. J Neurosci 20, 4198–205.
Schweizer A, Valdenaire O, Koster A et al. (1999) Neonatal lethality in mice deficient in XCE, a novel member of endothelin-converting enzyme and neutral endopeptidase family. J Biol Chem 274, 20450–6.
Shadiack AM, Sun Y, Zigmond RE (2001) Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurosci 21, 363–71.
Shirotani K, Tsubuki S, Iwata N et al. (2001) Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276, 21895–901.
Snider WD, McMahon SB (1998) Tackling pain at the source: New ideas about nociceptors. Neuron 20, 629–32.
Sumitomo M, Iwase A, Zheng R et al. (2004) Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN. Cancer Cell 5, 67–78.
Sun Y, Zigmond RE (1996) Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons. Eur J Neurosci 8, 2213–20.
Tanabe K, Nakagomi S, Kiryu-Seo S et al. (1999) Expressed- sequence-tag approach to identify differentially expressed genes following peripheral nerve axotomy. Mol Brain Res 64, 34–40.
Turner AJ, Tanzawa K (1997) Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB J 11, 355–64.
Valdenaire O, Schweizer A (2000) Endothelin-converting enzyme-like 1 (ECEL1; ‘XCE’): A putative metallopeptidase crucially involved in the nervous control of respiration. Biochem Soc Trans 28, 426–30.
Valdenaire O, Richards JG, Faull RL, Schweizer A (1999) XCE, a new member of the endothelin-converting enzyme and neutral endopeptidase family, is preferentially expressed in the CNS. Mol Brain Res 64, 211–21.
Valdenaire O, Rohrbacher E, Langeveld A, Schweizer A, Meijers C (2000) Organization and chromosomal localization of the human ECEL1 (XCE) gene encoding a zinc metallopeptidase involved in the nervous control of respiration. Biochem J 346, 611–16.
Zigmond RE (2001) Can galanin also be considered as growth-associated protein 3.2? Trends Neurosci 24, 494–6.
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Kiryu-Seo, S. Identification and functional analysis of damage-induced neuronal endopeptidase (DINE), a nerve injury associated molecule. Anato Sci Int 81, 1–6 (2006). https://doi.org/10.1111/j.1447-073X.2006.00136.x
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DOI: https://doi.org/10.1111/j.1447-073X.2006.00136.x