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

Thomas H Gillingwater; Thomas M Wishart; Philip E Chen; Jane Haley; Kevin Robertson; Stephen H-F MacDonald; Susan Middleton; Kolja Wawrowski; Michael J Shipston; Shlomo Melmed; David J A Wyllie; Paul A Skehel; Michael P Coleman; Richard R Ribchester

doi:10.1093/hmg/ddi478

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

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 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 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.

Original language	English
Pages (from-to)	625-35
Number of pages	11
Journal	Human Molecular Genetics
Volume	15
Issue number	4
DOIs	https://doi.org/10.1093/hmg/ddi478
Publication status	Published - 2006

Keywords

Animals
Cell Line
Gene Expression Regulation
Gene Targeting
Gene Therapy
Humans
Membrane Proteins
Mice
Mice, Transgenic
Neoplasm Proteins
Nerve Tissue Proteins
Neurons
Nicotinamide-Nucleotide Adenylyltransferase
Recombinant Fusion Proteins
Transfection
Tumor Suppressor Proteins
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases
Wallerian Degeneration
Wounds and Injuries

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10.1093/hmg/ddi478

1 Finished

The role of transcriptional regulation in axonal and synaptic neuroprotection conferred by the Wlds Gene.
Gillingwater, T.
BBSRC
1/10/05 → 31/07/09
Project: Research

Cite this

Gillingwater, T. H., Wishart, T. M., Chen, P. E., Haley, J., Robertson, K., MacDonald, S. H-F., Middleton, S., Wawrowski, K., Shipston, M. J., Melmed, S., Wyllie, D. J. A., Skehel, P. A., Coleman, M. P., & Ribchester, R. R. (2006). The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells. Human Molecular Genetics, 15(4), 625-35. https://doi.org/10.1093/hmg/ddi478

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

abstract = "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 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 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.",

keywords = "Animals, Cell Line, Gene Expression Regulation, Gene Targeting, Gene Therapy, Humans, Membrane Proteins, Mice, Mice, Transgenic, Neoplasm Proteins, Nerve Tissue Proteins, Neurons, Nicotinamide-Nucleotide Adenylyltransferase, Recombinant Fusion Proteins, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Wallerian Degeneration, Wounds and Injuries",

author = "Gillingwater, {Thomas H} and Wishart, {Thomas M} and Chen, {Philip E} and Jane Haley and Kevin Robertson and MacDonald, {Stephen H-F} and Susan Middleton and Kolja Wawrowski and Shipston, {Michael J} and Shlomo Melmed and Wyllie, {David J A} and Skehel, {Paul A} and Coleman, {Michael P} and Ribchester, {Richard R}",

year = "2006",

doi = "10.1093/hmg/ddi478",

language = "English",

volume = "15",

pages = "625--35",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

}

Gillingwater, TH , Wishart, TM, Chen, PE, Haley, J, Robertson, K, MacDonald, SH-F, Middleton, S, Wawrowski, K, Shipston, MJ, Melmed, S, Wyllie, DJA , Skehel, PA, Coleman, MP & Ribchester, RR 2006, 'The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells', Human Molecular Genetics, vol. 15, no. 4, pp. 625-35. https://doi.org/10.1093/hmg/ddi478

TY - JOUR

T1 - The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells

AU - Gillingwater, Thomas H

AU - Wishart, Thomas M

AU - Chen, Philip E

AU - Haley, Jane

AU - Robertson, Kevin

AU - MacDonald, Stephen H-F

AU - Middleton, Susan

AU - Wawrowski, Kolja

AU - Shipston, Michael J

AU - Melmed, Shlomo

AU - Wyllie, David J A

AU - Skehel, Paul A

AU - Coleman, Michael P

AU - Ribchester, Richard R

PY - 2006

Y1 - 2006

N2 - 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 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 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.

AB - 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 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 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.

KW - Animals

KW - Cell Line

KW - Gene Expression Regulation

KW - Gene Targeting

KW - Gene Therapy

KW - Humans

KW - Membrane Proteins

KW - Mice

KW - Mice, Transgenic

KW - Neoplasm Proteins

KW - Nerve Tissue Proteins

KW - Neurons

KW - Nicotinamide-Nucleotide Adenylyltransferase

KW - Recombinant Fusion Proteins

KW - Transfection

KW - Tumor Suppressor Proteins

KW - Ubiquitin-Protein Ligase Complexes

KW - Ubiquitin-Protein Ligases

KW - Wallerian Degeneration

KW - Wounds and Injuries

U2 - 10.1093/hmg/ddi478

DO - 10.1093/hmg/ddi478

M3 - Article

C2 - 16403805

VL - 15

SP - 625

EP - 635

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -

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

Abstract

Keywords

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The role of transcriptional regulation in axonal and synaptic neuroprotection conferred by the Wlds Gene.

Cite this