MAB21L1 modulates gene expression and DNA metabolic processes in the lens placode

  • Ryuichi Yamada
    Department of Veterinary Anatomy, the University of Tokyo, Tokyo 113-8657, Japan
  • Akira Oguri
    Department of Applied Biological Chemistry, the University of Tokyo, Tokyo 113-8657, Japan
  • Katsunori Fujiki
    Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, the University of Tokyo, Tokyo 113-0032, Japan
  • Katsuhiko Shirahige
    Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, the University of Tokyo, Tokyo 113-0032, Japan
  • Yoshikazu Hirate
    Department of Experimental Animal Model for Human Disease, Center for Experimental Animals, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
  • Masami Kanai-Azuma
    Department of Experimental Animal Model for Human Disease, Center for Experimental Animals, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
  • Hirotaka Takezoe
    Genble Inc., Fukuoka 814-0001, Japan
  • Yoshihiro Akimoto
    Department of Anatomy, Kyorin University School of Medicine, Tokyo 181-8611, Japan
  • Naoki Takahashi
    Department of Applied Biological Chemistry, the University of Tokyo, Tokyo 113-8657, Japan
  • Yoshiakira Kanai
    Department of Veterinary Anatomy, the University of Tokyo, Tokyo 113-8657, Japan

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<jats:title>ABSTRACT</jats:title> <jats:p>Mutations in human MAB21L1 cause aberrations in lens ectoderm morphogenesis and lead to congenital cerebellar, ocular, craniofacial and genital (COFG) syndrome. Murine Mab21l1-null mutations cause severe cell-autonomous defects in lens formation, leading to microphthalmia; therefore, Mab21l1-null mice are used as a mouse model for COFG syndrome. In this study, we investigated the early-onset single-cell-level phenotypes of murine Mab21l1-null lens ectoderms using electron microscopy and single-cell RNA sequencing (scRNA-seq). Electron microscopy and immunohistochemical analyses indicated endoplasmic reticulum stress at the 24- to 26-somite stage in Mab21l1-null lens placodes. scRNA-seq analysis revealed that 131 genes were downregulated and 148 were upregulated in Mab21l1-null lens ectoderms relative to the wild type. We successfully identified 21 lens-specific genes that were downregulated in Mab21l1-null cells, including three key genes involved in lens formation: Pitx3, Maf and Sfrp2. Moreover, gene ontology analysis of the 279 differentially expressed genes indicated enrichment in housekeeping genes associated with DNA/nucleotide metabolism prior to cell death. These findings suggest that MAB21L1 acts as a nuclear factor that modulates not only lens-specific gene expression but also DNA/nucleotide metabolic processes during lens placode formation.</jats:p>

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