Qiming Xu , Lijia Cui , Yude Lin , Leigh-Anne Cui , Weibo Xia
{"title":"Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene","authors":"Qiming Xu , Lijia Cui , Yude Lin , Leigh-Anne Cui , Weibo Xia","doi":"10.1016/j.bonr.2024.101746","DOIUrl":null,"url":null,"abstract":"<div><p>Filamin B (FLNB) plays an important role in skeletal development. Mutations in <em>FLNB</em> can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation <em>FLNB</em> NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. <em>In situ</em> hybridization of embryos was performed to examine the transcription of <em>HOX</em> genes during embryonic development. The expression of <em>FLNB</em> was downregulated in <em>FLNB</em><sup><em>G1586R/G1586R</em></sup> and <em>FLNB</em><sup><em>WT/G1586R</em></sup> mice, compared to <em>FLNB</em><sup><em>WT/WT</em></sup> mice. Fusions in tarsal bones were found in <em>FLNB</em><sup><em>G1586R/G1586R</em></sup> and <em>FLNB</em><sup><em>WT/G1586R</em></sup> mice, indicating that the skeletal segmentation was interfered with. In the embryo of <em>FLNB</em><sup><em>G1586R</em>/<em>G1586R</em></sup> mice (E12.5), the transcription levels of <em>HOXD10</em> and <em>HOXB2</em> were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in <em>FLNB</em> may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of <em>HOX</em> gene transcription during the embryonic period.</p></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"20 ","pages":"Article 101746"},"PeriodicalIF":2.1000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352187224000135/pdfft?md5=728bb9d200c17274480dd8ba735f03ab&pid=1-s2.0-S2352187224000135-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2352187224000135","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNBG1586R/G1586R and FLNBWT/G1586R mice, compared to FLNBWT/WT mice. Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNBG1586R/G1586R mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period.
Bone ReportsMedicine-Orthopedics and Sports Medicine
CiteScore
4.30
自引率
4.00%
发文量
444
审稿时长
57 days
期刊介绍:
Bone Reports is an interdisciplinary forum for the rapid publication of Original Research Articles and Case Reports across basic, translational and clinical aspects of bone and mineral metabolism. The journal publishes papers that are scientifically sound, with the peer review process focused principally on verifying sound methodologies, and correct data analysis and interpretation. We welcome studies either replicating or failing to replicate a previous study, and null findings. We fulfil a critical and current need to enhance research by publishing reproducibility studies and null findings.