Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mice.

Abstract

Damage of oligodendrocytes after ischemia has negative impact on white matter integrity and neuronal function. In this work, we explore whether Netrin-1 (NT-1) overexpression facilitates white matter repairing and remodeling. Adult CD-1 mice received stereotactic injection of adeno-associated virus carrying NT-1 gene (AAV-NT-1). One week after gene transfer, mice underwent 60 minutes of middle cerebral artery occlusion. The effect of NT-1 on neural function was evaluated by neurobehavioral tests. Proliferated oligodendrocyte progenitor cells (OPCs), newly matured oligodendrocytes, and remyelination were semi-quantified by immunohistochemistry. The role of NT-1 in oligodendrogenesis was further explored by examining specific NT-1 receptors and their function. Netrin-1 overexpression was detected in neurons and astrocytes 2 weeks after AAV-NT-1 gene transfer and significantly improved the neurobehavioral outcomes compared with the control (P<0.05). In comparison with the control, proliferated OPCs, newly matured oligodendrocytes, and remyelination were greatly increased in the ipsilateral hemisphere of AAV-NT-1-transduced mice. Furthermore, both NT-1 receptors deleted in colorectal carcinoma and UNC5H2 were expressed on OPCs whereas only UNC5H2 was expressed in myelinated axons. Our study indicated that NT-1 promoted OPC proliferation, differentiation, and increased remyelination, suggesting that NT-1 is a promising factor for white matter repairing and remodeling after ischemia.

• Authors: Xiaosong He, Yaning Li, Haiyan Lu, Zhijun Zhang, Yongting Wang, Guo-Yuan Yang
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 33 Issue 12 Pg. 1921-7 (Dec 2013) ISSN: 1559-7016 [Electronic] United States
• PMID: 23963365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Growth Factors
• Ntn1 protein, mouse
• Tumor Suppressor Proteins
• Netrin-1

Topics

• Adenoviridae (genetics)
• Animals
• Brain (metabolism, pathology, physiopathology)
• Brain Ischemia (genetics, pathology, physiopathology, therapy)
• Cell Proliferation
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors (genetics, therapeutic use)
• Male
• Mice
• Myelin Sheath (metabolism, pathology)
• Nerve Growth Factors (genetics)
• Netrin-1
• Oligodendroglia (cytology, metabolism, pathology)
• Stem Cells (cytology, metabolism, pathology)
• Tumor Suppressor Proteins (genetics)
• Up-Regulation