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The Journal of Neuroscience, July 5, 2006, 26(27):7234-7244; doi:10.1523/JNEUROSCI.1398-06.2006

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Neurobiology of Disease
Nedd4-WW Domain-Binding Protein 5 (Ndfip1) Is Associated with Neuronal Survival after Acute Cortical Brain Injury

Qian Sang,¹ Mary H. Kim,¹ Sharad Kumar,³ Nicole Bye,² Maria C. Morganti-Kossman,² Jenny Gunnersen,¹ Stephanie Fuller,¹ Jason Howitt,¹ Lavinia Hyde,⁴ Tim Beissbarth,⁴ Hamish S. Scott,⁴ John Silke,⁴ and Seong-Seng Tan¹

¹Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia, ²Trauma Research Institute, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia, ³Hanson Center for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, South Australia 5000, Australia, and ⁴Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia

Correspondence should be addressed to Seong-Seng Tan, Brain Development Laboratory, Howard Florey Institute, The University of Melbourne, Parkville 3010, Victoria, Australia. Email: stan{at}hfi.unimelb.edu.au

Understanding the transcriptional response to neuronal injury after trauma is a necessary prelude to formulation of therapeutic strategies. We used Serial Analysis of Gene Expression (SAGE) to identify 50,000 sequence tags representing 18,000 expressed genes in the cortex 2 h after traumatic brain injury (TBI). A similar tag library was obtained from sham-operated cortex. The SAGE data were validated on biological replicates using quantitative real-time-PCR on multiple samples at 2, 6, 12, and 24 h after TBI. This analysis revealed that the vast majority of genes showed a downward trend in their pattern of expression over 24 h. This was confirmed for a subset of genes using in situ hybridization and immunocytochemistry on brain sections. Of the overexpressed genes in the trauma library, Nedd4-WW (neural precursor cell expressed, developmentally downregulated) domain-binding protein 5 (N4WBP5) (also known as Ndfip1) is strongly expressed in surviving neurons around the site of injury. Overexpression of N4WBP5 in cultured cortical neurons increased the number of surviving neurons after gene transfection and growth factor starvation compared with control transfections. These results identify N4WBP5 as a neuroprotective protein and, based on its known interaction with the ubiquitin ligase Nedd4, would suggest protein ubiquitination as a possible survival strategy in neuronal injury.

Key words: traumatic brain injury; cerebral cortex; SAGE; ubiquitination; differential gene expression; apoptosis

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Received Jan. 9, 2006; revised May 21, 2006; accepted May 25, 2006.

Correspondence should be addressed to Seong-Seng Tan, Brain Development Laboratory, Howard Florey Institute, The University of Melbourne, Parkville 3010, Victoria, Australia. Email: stan{at}hfi.unimelb.edu.au

This article has been cited by other articles:

				J. Howitt, U. Putz, J. Lackovic, A. Doan, L. Dorstyn, H. Cheng, B. Yang, T. Chan-Ling, J. Silke, S. Kumar, et al. Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons PNAS, September 8, 2009; 106(36): 15489 - 15494. [Abstract] [Full Text] [PDF]

				U. Putz, J. Howitt, J. Lackovic, N. Foot, S. Kumar, J. Silke, and S.-S. Tan Nedd4 Family-interacting Protein 1 (Ndfip1) Is Required for the Exosomal Secretion of Nedd4 Family Proteins J. Biol. Chem., November 21, 2008; 283(47): 32621 - 32627. [Abstract] [Full Text] [PDF]

				J. A. Sullivan, M. J. Lewis, E. Nikko, and H. R.B. Pelham Multiple Interactions Drive Adaptor-Mediated Recruitment of the Ubiquitin Ligase Rsp5 to Membrane Proteins In Vivo and In Vitro Mol. Biol. Cell, July 1, 2007; 18(7): 2429 - 2440. [Abstract] [Full Text] [PDF]

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