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Human Molecular Genetics Advance Access originally published online on January 10, 2006
Human Molecular Genetics 2006 15(4):625-635; doi:10.1093/hmg/ddi478
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells

Thomas H. Gillingwater1,2,*,{dagger}, Thomas M. Wishart1,{dagger}, Philip E. Chen1, Jane E. Haley1, Kevin Robertson3, Stephen H.-F. MacDonald2, Susan Middleton1, Kolja Wawrowski4, Michael J. Shipston2, Shlomo Melmed4, David J.A. Wyllie1, Paul A. Skehel1, Michael P. Coleman5 and Richard R. Ribchester1

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

* To whom correspondence should be addressed. Tel: +44 1316503724; Fax: +44 1316506545; Email: t.gillingwater{at}ed.ac.uk

Received October 7, 2005; Revised November 23, 2005; Accepted January 4, 2006

Wallerian degeneration of injured neuronal axons and synapses is blocked in WldS mutant mice by expression of an nicotinamide mononucleotide adenylyl transferase 1 (Nmnat-1)/truncated-Ube4b chimeric gene. The protein product of the WldS gene localizes 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) cells in vitro. The largest changes, identified by microarray analysis and quantitative real-time polymerase chain reaction 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 1 mM nicotinamide adenine dinucleotide (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 pttg1 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 subset 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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