Heterozygous mutation of the splicing factor <scp><i>Sf3b4</i></scp> affects development of the axial skeleton and forebrain in mouse

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  • Takahiko Yamada
    Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Masaki Takechi
    Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Norisuke Yokoyama
    Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Yuichi Hiraoka
    Laboratory of Genome Editing for Biomedical Research Medical Research Institute, Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Harumi Ishikubo
    Laboratory of Genome Editing for Biomedical Research Medical Research Institute, Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Takako Usami
    Laboratory of Genome Editing for Biomedical Research Medical Research Institute, Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Toshiko Furutera
    Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Yuki Taga
    Nippi Research Institute of Biomatrix Ibaraki Japan
  • Yoshikazu Hirate
    Department of Experimental Animal Model for Human Disease, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Masami Kanai‐Azuma
    Department of Experimental Animal Model for Human Disease, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Tetsuya Yoda
    Section of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan
  • Kiyoko Ogawa‐Goto
    Nippi Research Institute of Biomatrix Ibaraki Japan
  • Sachiko Iseki
    Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan

説明

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Splicing factor 3B subunit 4 (<jats:italic>SF3B4</jats:italic>) is a causative gene of an acrofacial dysostosis, Nager syndrome. Although in vitro analyses of <jats:italic>SF3B4</jats:italic> have proposed multiple noncanonical functions unrelated to splicing, less information is available based on in vivo studies using model animals.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We performed expression and functional analyses of <jats:italic>Sf3b4</jats:italic> in mice. The mouse <jats:italic>Sf3b4</jats:italic> transcripts were found from two‐cell stage, and were ubiquitously present during embryogenesis with high expression levels in several tissues such as forming craniofacial bones and brain. In contrast, expression of a pseudogene‐like sequence of mouse <jats:italic>Sf3b4</jats:italic> (<jats:italic>Sf3b4_ps</jats:italic>) found by in silico survey was not detected up to embryonic day 10. We generated a <jats:italic>Sf3b4</jats:italic> knockout mouse using CRISPR‐Cas9 system. The homozygous mutant mouse of <jats:italic>Sf3b4</jats:italic> was embryonic lethal. The heterozygous mutant of <jats:italic>Sf3b4</jats:italic> mouse (<jats:italic>Sf3b4</jats:italic><jats:sup>+/−</jats:sup>) exhibited smaller body size compared to the wild‐type from postnatal to adult period, as well as homeotic posteriorization of the vertebral morphology and flattened calvaria. The flattened calvaria appears to be attributable to mild microcephaly due to a lower cell proliferation rate in the forebrain.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our study suggests that <jats:italic>Sf3b4</jats:italic> controls anterior‐posterior patterning of the axial skeleton and guarantees cell proliferation for forebrain development in mice.</jats:p></jats:sec>

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