Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease

Kevin Sun, Xiao Li, Xing Chen, Ying Bai, Gao Zhou, Olga N. Kokiko-Cochran, Bruce Lamb, Thomas A. Hamilton, Ching Yi Lin, Yu Shang Lee, Tomasz Herjan

Research output: Contribution to journalArticle

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Abstract

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and a motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament–binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.

Original languageEnglish (US)
Pages (from-to)157-166
Number of pages10
JournalJournal of Immunology
Volume201
Issue number1
DOIs
StatePublished - Jul 1 2018
Externally publishedYes

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Motor Neuron Disease
Neurons
Brain
Caspase 3
Rotarod Performance Test
vpr Genes
Gene Components
Gene Ontology
RNA-Binding Proteins
Forelimb
Pyramidal Cells
Amyotrophic Lateral Sclerosis
Motor Neurons
Hand Strength
Tamoxifen
Keratins
GTP-Binding Proteins
Real-Time Polymerase Chain Reaction
Spinal Cord
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Sun, K., Li, X., Chen, X., Bai, Y., Zhou, G., Kokiko-Cochran, O. N., ... Herjan, T. (2018). Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. Journal of Immunology, 201(1), 157-166. https://doi.org/10.4049/jimmunol.1701501

Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. / Sun, Kevin; Li, Xiao; Chen, Xing; Bai, Ying; Zhou, Gao; Kokiko-Cochran, Olga N.; Lamb, Bruce; Hamilton, Thomas A.; Lin, Ching Yi; Lee, Yu Shang; Herjan, Tomasz.

In: Journal of Immunology, Vol. 201, No. 1, 01.07.2018, p. 157-166.

Research output: Contribution to journalArticle

Sun, K, Li, X, Chen, X, Bai, Y, Zhou, G, Kokiko-Cochran, ON, Lamb, B, Hamilton, TA, Lin, CY, Lee, YS & Herjan, T 2018, 'Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease', Journal of Immunology, vol. 201, no. 1, pp. 157-166. https://doi.org/10.4049/jimmunol.1701501
Sun K, Li X, Chen X, Bai Y, Zhou G, Kokiko-Cochran ON et al. Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. Journal of Immunology. 2018 Jul 1;201(1):157-166. https://doi.org/10.4049/jimmunol.1701501
Sun, Kevin ; Li, Xiao ; Chen, Xing ; Bai, Ying ; Zhou, Gao ; Kokiko-Cochran, Olga N. ; Lamb, Bruce ; Hamilton, Thomas A. ; Lin, Ching Yi ; Lee, Yu Shang ; Herjan, Tomasz. / Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. In: Journal of Immunology. 2018 ; Vol. 201, No. 1. pp. 157-166.
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abstract = "Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and a motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament–binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.",
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