RESEARCH ARTICLE

Overexpression of netrin-1 improves neurological outcomes in mice following transient middle cerebral artery occlusion

  • Haiyan LU 1 ,
  • Yongting WANG 1 ,
  • Falei YUAN 1 ,
  • Jianrong LIU 2 ,
  • Lili ZENG 1,2 ,
  • Guo-Yuan YANG , 1,2
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  • 1. Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
  • 2. Departments of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China

Received date: 16 Dec 2010

Accepted date: 21 Jan 2011

Published date: 05 Mar 2011

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Netrin-1 (NT-1) is one of the axon-guiding molecules that are critical for neuronal development. Because of its structural homology to the endothelial mitogens, NT-1 may have similar effects on vascular network formation. NT-1 was shown to be able to stimulate the proliferation and migration of human cerebral endothelial cells in vitro and also promote focal neovascularization in adult brain in vivo. In the present study, we reported the delivery of NT-1 using an adeno-associated virus (AAV) vector (AAV-NT-1) into mouse brain followed by transient middle cerebral artery occlusion (tMCAO). We found that AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage after brain transduction. The level of NT-1 was increased in the AAV-NT-1-transduced tMCAO mice compared with the control mice. Furthermore, the neurobehavioral outcomes were significantly improved in AAV-NT-1-transduced mice compared with the control animals (P<0.05) 7 days after tMCAO. Our data suggests that NT-1 plays a neuronal function recovery role in ischemic brain and that NT-1 gene transfer might present a valuable approach to treat brain ischemic disorders.

Cite this article

Haiyan LU , Yongting WANG , Falei YUAN , Jianrong LIU , Lili ZENG , Guo-Yuan YANG . Overexpression of netrin-1 improves neurological outcomes in mice following transient middle cerebral artery occlusion[J]. Frontiers of Medicine, 2011 , 5(1) : 86 -93 . DOI: 10.1007/s11684-011-0118-x

Acknowledgments

This study is supported by the National Basic Research Program 2011CB504405 (Guo-yuan yang, Yongting Wang) and the National Natural Science Foundation of China (#30973097). The authors thank Ms. Karana Shun and Yan Wang for their editorial assistance and staff of the Neuroscience and Neuroengineering Center for their collaborative support.
1
Kennedy T E, Serafini T, de la Torre JR, Tessier-LavigneM. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell, 1994, 78(3): 425-435

DOI

2
Kennedy T E, Tessier-Lavigne M. Guidance and induction of branch formation in developing axons by target-derived diffusible factors. Curr Opin Neurobiol, 1995, 5(1): 83-90

DOI

3
Leonardo E D, Hinck L, Masu M, Keino-Masu K, Ackerman S L, Tessier-Lavigne M. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature, 1997, 386(6627): 833-838

DOI

4
Stein E, Zou Y. Poo, M, Tessier-Lavigne, M. Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation. Science, 2001, 291(5510): 1976-1982

DOI

5
Guthrie S. Axon guidance: netrin receptors are revealed. Curr Biol, 1997, 7(1): R6-R9

DOI PMID

6
Kennedy T E. Cellular mechanisms of netrin function: long-range and short-range actions. Biochem Cell Biol, 2000, 78(5): 569-575

DOI PMID

7
Harris R, Sabatelli L M, Seeger, M A. Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron, 1996, 17(2): 217-228

DOI

8
Forcet C, Stein E, Pays L, Corset V, Llambi F, Tessier-Lavigne M, Mehlen P. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature, 2002, 417(6887): 443-447

DOI

9
Llambi F, Causeret F. Bloch-Gallego E, Mehlen, P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J, 2001, 20(11): 2715-2722

DOI

10
Mehlen P, Llambi F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers. Br J Cancer, 2005, 93(1): 1-6

11
Lu X, Le Noble F, Yuan L, Jiang Q, De Lafarge B, Sugiyama D, Breant C, Claes F, De Smet F, Thomas J L, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature, 2004, 432 (7014): 179-186

DOI

12
Park K W, Crouse D, Lee M, Karnik S K, Sorensen L K, Murphy K J, Kuo C J, Li D Y. The axonal attractant Netrin-1 is an angiogenic factor. Proc Natl Acad Sci USA, 2004, 101(46): 16210-16215

DOI

13
Fan Y, Shen F, Chen Y, Liu W, Su H, Young W L, Yang G Y. Overexpression of Netrin-1 induces neovascularization in the adult mouse brain. J Cereb Blood Flow Metab, 2008, 28(9):1543-1551

14
Vincent-Lacaze N, Snyder R O, Gluzman R, Bohl D. Lagarde C, Danos O. Structure of adeno-associated virus vector DNA following transduction of the skeletal muscle. J Virol, 1999, 73(3): 1949-1955

15
Snyder R O, Spratt S K, Lagarde C, Bohl D, Kaspar B, Sloan B, Cohen L, Danos O K. Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. Hum Gene Ther, 1997, 8(16): 1891-1900

DOI

16
Shen F, Su H, Liu W, Kan Y W, Young W L, Yang G Y. Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain. Front Biosci, 2006, 11: 3190-3198

17
Tenenbaum L, Chtarto A, Lehtonen E, Velu T, Brotchi J, Levivier M. Recombinant AAV-mediated gene delivery to the central nervous system. J Gene Med, 2004, 6 Suppl 1: S212-S222

18
Yang G Y, Chan P H, Chen J, Carlson E, Chen S F, Weinstein P, Epstein C J, Kamii H. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke, 1994, 25: 165-170

19
Yang G Y, Zhao Y, Davidson B L, Betz A L. Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res, 1997, 751: 181-188

20
Chang J H, Gabison E E, Kato T, Azar D. Corneal neovascularization. Curr Opin Ophthalmol, 2001, 12(4): 242-249

DOI

21
Lee C Z, Xu B, Hashimoto T, McCulloch C E, Yang G, Young W L. Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model. Stroke, 2004, 35(7): 1715-1719

DOI

22
Yang G Y, Xu B, Hashimoto T, Huey M, Chaly T Jr, Wen R, Young W L. Induction of focal angiogenesis through adenoviral vector mediated vascular endothelial cell growth factor gene transfer in the mature mouse brain. Angiogenesis, 2003, 6(2): 151-158

DOI

23
Chen Y, Xu B, Arderiu G, Hashimoto T, Young W L, Boudreau N, Yang G Y. Retroviral delivery of homeobox d3 gene induces cerebral angiogenesis in mice. J Cereb Blood Flow Metab, 2004, 24(11): 1280-1287

DOI

24
Xiao X, Li, J, Samulski R J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol, 1996, 70(11): 8098-8108

25
McCown T J. Adeno-associated virus (AAV) vectors in the CNS. Curr Gene Ther, 2005, 5(3): 333-338

DOI PMID

26
Serafini T, Colamarino S A, Leonardo E D, Wang H, Beddington R, Skarnes W C, Tessier-Lavigne M. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell, 1996, 87(6): 1001-1014

DOI

27
Xie Y, Hong Y, Ma X Y, Ren X R, Ackerman S, Mei L, Xiong W C. DCC-dependent phospholipase C signaling in netrin-1-induced neurite elongation. J Biol Chem, 2006, 281(5): 2605-2611

28
Barallobre M J, Pascual M, Del Rio J, Soriano E. The Netrin family of guidance factors: emphasis on Netrin-1 signalling. Brain Res Brain Res Rev, 2005, 49(1): 22-47

DOI

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