TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy
Abstract Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C +/+) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monito...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-07468-2 |
| _version_ | 1818842120316780544 |
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| author | Matthew D. Howell Eric W. Ottesen Natalia N. Singh Rachel L. Anderson Joonbae Seo Senthilkumar Sivanesan Elizabeth M. Whitley Ravindra N. Singh |
| author_facet | Matthew D. Howell Eric W. Ottesen Natalia N. Singh Rachel L. Anderson Joonbae Seo Senthilkumar Sivanesan Elizabeth M. Whitley Ravindra N. Singh |
| author_sort | Matthew D. Howell |
| collection | DOAJ |
| description | Abstract Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C +/+) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific. We show that female Tia1-knockout (Tia1 −/−) mice gain significant body weight (BW) during early postnatal development. We next examined the effect of Tia1 deletion in novel C +/+/Tia1 −/− mice. Underscoring the opposing effects of Tia1 deletion and low SMN level on BW gain, both C +/+ and C +/+/Tia1 −/− females showed similar BW gain trajectory at all time points during our study. We observed early tail necrosis in C +/+/Tia1 −/− females but not in males. We show enhanced impairment of male reproductive organ development and exacerbation of the C +/+/Tia1 −/− testis transcriptome. Our findings implicate a protein factor as a gender-specific modifier of a mild mouse model of SMA. |
| first_indexed | 2024-12-19T04:36:55Z |
| format | Article |
| id | doaj.art-52d3ab15d6f44118a9db9e9a35596a5b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:36:55Z |
| publishDate | 2017-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-52d3ab15d6f44118a9db9e9a35596a5b2022-12-21T20:35:44ZengNature PortfolioScientific Reports2045-23222017-08-017111810.1038/s41598-017-07468-2TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophyMatthew D. Howell0Eric W. Ottesen1Natalia N. Singh2Rachel L. Anderson3Joonbae Seo4Senthilkumar Sivanesan5Elizabeth M. Whitley6Ravindra N. Singh7Department of Biomedical Sciences, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityDepartment of Veterinary Pathology, Iowa State UniversityDepartment of Biomedical Sciences, Iowa State UniversityAbstract Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C +/+) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific. We show that female Tia1-knockout (Tia1 −/−) mice gain significant body weight (BW) during early postnatal development. We next examined the effect of Tia1 deletion in novel C +/+/Tia1 −/− mice. Underscoring the opposing effects of Tia1 deletion and low SMN level on BW gain, both C +/+ and C +/+/Tia1 −/− females showed similar BW gain trajectory at all time points during our study. We observed early tail necrosis in C +/+/Tia1 −/− females but not in males. We show enhanced impairment of male reproductive organ development and exacerbation of the C +/+/Tia1 −/− testis transcriptome. Our findings implicate a protein factor as a gender-specific modifier of a mild mouse model of SMA.https://doi.org/10.1038/s41598-017-07468-2 |
| spellingShingle | Matthew D. Howell Eric W. Ottesen Natalia N. Singh Rachel L. Anderson Joonbae Seo Senthilkumar Sivanesan Elizabeth M. Whitley Ravindra N. Singh TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy Scientific Reports |
| title | TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy |
| title_full | TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy |
| title_fullStr | TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy |
| title_full_unstemmed | TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy |
| title_short | TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy |
| title_sort | tia1 is a gender specific disease modifier of a mild mouse model of spinal muscular atrophy |
| url | https://doi.org/10.1038/s41598-017-07468-2 |
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