Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene

IF 2.1 Q3 ENDOCRINOLOGY & METABOLISM Bone Reports Pub Date : 2024-03-01 DOI:10.1016/j.bonr.2024.101746
Qiming Xu , Lijia Cui , Yude Lin , Leigh-Anne Cui , Weibo Xia
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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.

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FLNB 基因的中断会通过 HOX 基因干扰骨骼的分割,从而导致骨骼畸形
纤 维素 B(FLNB)在骨骼发育过程中发挥着重要作用。FLNB突变可导致骨骼畸形,如骨化中心数量异常,这表明胚胎时期的骨骼分割可能受到干扰。我们利用CRISPR-Cas9技术建立了致病点突变FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) 的小鼠模型。为检测骨骼畸形,对胚胎进行了显微 CT、HE 染色和全骨骼制备。对胚胎进行原位杂交以检测胚胎发育过程中HOX基因的转录情况。与FLNBWT/WT小鼠相比,FLNBG1586R/G1586R和FLNBWT/G1586R小鼠中FLNB的表达下调。在FLNBG1586R/G1586R和FLNBWT/G1586R小鼠中发现跗骨融合,这表明骨骼的分割受到了干扰。在FLNBG1586R/G1586R小鼠胚胎(E12.5)中,HOXD10和HOXB2的转录水平分别在腕骨区和颈椎区下调。该研究表明,FLNB功能缺失突变G1586R可能导致骨骼分割异常,其机制可能与胚胎期HOX基因转录下调有关。
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来源期刊
Bone Reports
Bone Reports Medicine-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.
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