Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality
Summary: Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enh...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724002353 |
| _version_ | 1827321770334486528 |
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| author | Aki Ushiki Rory R. Sheng Yichi Zhang Jingjing Zhao Mai Nobuhara Elizabeth Murray Xin Ruan Jonathan J. Rios Carol A. Wise Nadav Ahituv |
| author_facet | Aki Ushiki Rory R. Sheng Yichi Zhang Jingjing Zhao Mai Nobuhara Elizabeth Murray Xin Ruan Jonathan J. Rios Carol A. Wise Nadav Ahituv |
| author_sort | Aki Ushiki |
| collection | DOAJ |
| description | Summary: Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism. |
| first_indexed | 2024-04-25T01:12:53Z |
| format | Article |
| id | doaj.art-bd9e040e216d463ca06508bc1cda0996 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-25T01:12:53Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-bd9e040e216d463ca06508bc1cda09962024-03-10T05:12:07ZengElsevierCell Reports2211-12472024-03-01433113907Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormalityAki Ushiki0Rory R. Sheng1Yichi Zhang2Jingjing Zhao3Mai Nobuhara4Elizabeth Murray5Xin Ruan6Jonathan J. Rios7Carol A. Wise8Nadav Ahituv9Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USACenter for Translational Research, Scottish Rite for Children, Dallas, TX 75390, USA; Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Research, Scottish Rite for Children, Dallas, TX 75390, USA; Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding authorSummary: Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.http://www.sciencedirect.com/science/article/pii/S2211124724002353CP: Molecular biology |
| spellingShingle | Aki Ushiki Rory R. Sheng Yichi Zhang Jingjing Zhao Mai Nobuhara Elizabeth Murray Xin Ruan Jonathan J. Rios Carol A. Wise Nadav Ahituv Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality Cell Reports CP: Molecular biology |
| title | Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality |
| title_full | Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality |
| title_fullStr | Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality |
| title_full_unstemmed | Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality |
| title_short | Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality |
| title_sort | deletion of pax1 scoliosis associated regulatory elements leads to a female biased tail abnormality |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724002353 |
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