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

Wallerian degeneration of injured neuronal axons and synapses is blocked in Wld S mutant mice by expression of an nicotinamide mononucleotide adenylyl transferase 1 ( Nmnat-1 )/truncated- Ube4b chimeric gene. The protein product of the Wld S gene localizes to neuronal nuclei. Here we show that Wld S protein expression selectively alters mRNA levels of other genes in Wld S 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 Wld S - eGFP construct produced similar changes in mRNA levels for these and seven other genes, suggesting that regulation of gene expression by Wld S is conserved across different species, including humans. Similar modifications in mRNA levels were mimicked for some of the genes (including pttg1 ) by 1 m M nicotinamide adenine dinucleotide (NAD). However, expression levels of most other genes (including edr1l-EST ) were insensitive to NAD. Pttg1 2 / 2 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 Wld S . Together, the data suggest that the Wld S protein co-regulates expression of a consistent subset of genes in both mouse neurons and human cells. Targeting Wld S -induced gene expression may lead to novel therapies for neurodegeneration induced by trauma or by disease in humans.

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