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Human Molecular Genetics Advance Access published online on January 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi478
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received October 7, 2005
Revised November 23, 2005
Accepted January 4, 2006

Article

The Neuroprotective Wlds Gene Regulates Expression of PTTG1 and Erythroid Differentiation Regulator 1-Like Gene in Mice and Human Cells

Thomas H. Gillingwater 1 *, Thomas M. Wishart 2, Philip E. Chen 2, Jane E. Haley 2, Kevin Robertson 3, Stephen H-F. MacDonald 4, Susan Middleton 2, Kolja Wawrowski 5, Michael J. Shipston 4, Shlomo Melmed 5, David J.A. Wyllie 2, Paul A. Skehel 2, Michael P. Coleman 6, and Richard R. Ribchester 2

1 Centre for Neuroscience Research, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK; Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK
2 Centre for Neuroscience Research, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK
3 Scottish Centre for Genomic Technology and Informatics, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
4 Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK
5 Burns and Allen Research Institute, Cedars-Sinai Medical Centre, Los Angeles, CA, USA
6 The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

* To whom correspondence should be addressed.
Thomas H. Gillingwater, E-mail: T.Gillingwater{at}ed.ac.uk


  Abstract

Wallerian degeneration of injured neuronal axons and synapses is blocked in WldS mutant mice by expression of an Nmnat-1/truncated-Ube4b chimeric gene. The protein product of the WldS gene localises to neuronal nuclei. Here we show that WldS protein expression selectively alters mRNA levels of other genes in WldS mouse cerebellum in vivo and following transfection of human embryonic kidney (HEK293) in vitro. The largest changes, identified by microarray analysis and quantitative real-time PCR of cerebellar mRNA, were an approximate 10-fold down-regulation of pituitary tumour transforming gene-1 (pttg1) and an approximate 5-fold up-regulation of a structural homologue of erythroid differentiation regulator-1 (edr1l-EST). Transfection of HEK293 cells with a WldS-eGFP construct produced similar changes in mRNA levels for these and seven other genes, suggesting that regulation of gene expression by Wlds is conserved across different species, including humans. Similar modifications in mRNA levels were mimicked for some of the genes (including pttg1) by 1mM NAD. However, expression levels of most other genes (including edr1l-EST) were insensitive to NAD. Pttg1 -/- mutant mice showed no neuroprotective phenotype. Transfection of HEK293 cells with constructs comprising either full length Nmnat-1 or the truncated Ube4b fragment (N70-Ube4b) demonstrated selective effects of Nmnat-1 (down-regulated pttg1) and N70-Ube4b (up-regulated edr1l-EST) on mRNA levels. Similar changes in pttg-1 and edr1l-EST were observed in the mouse NSC34 motor neuron-like cell line following stable transfection with WldS. Together, the data suggest that the WldS protein co-regulates expression of a consistent sub-set of genes in both mouse neurons and human cells. Targeting WldS-induced gene expression may lead to novel therapies for neurodegeneration induced by trauma or by disease in humans.


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