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<p>DNA replication and repair are basic yet essential molecular processes for all cells. <i>RFC1</i> encodes the largest subunit of the Replication Factor C, an essential clamp-loader for DNA replication and repair. Intronic repeat expansion in <i>RFC1</i> has recently been associated with so-called <i>RFC1</i>-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms making certain tissues more susceptible to defects in these universal pathways remain mysterious. Here, we provide the first investigation of <i>RFC1</i> gene function in vivo using zebrafish. We showed that <i>RFC1</i> is expressed in neural progenitor cells within the developing cerebellum, where it maintains their genomic integrity during neurogenic maturation. Accordingly, <i>RFC1</i> loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data point to a specific role of <i>RFC1</i> in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlying <i>RFC1</i>-related disorders.</p>

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RFC1 regulates the expansion of neural progenitors in the developing zebrafish cerebellum

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

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  • Fanny Nobilleau,
  • Sébastien Audet,
  • Alexandra da Silva Babinet,
  • Sanaa Tork,
  • Charlotte Zaouter,
  • Meijiang Liao,
  • Nicolas Pilon,
  • Martine Tétreault,
  • Shunmoogum A. Patten,
  • Éric Samarut

摘要

DNA replication and repair are basic yet essential molecular processes for all cells. RFC1 encodes the largest subunit of the Replication Factor C, an essential clamp-loader for DNA replication and repair. Intronic repeat expansion in RFC1 has recently been associated with so-called RFC1-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms making certain tissues more susceptible to defects in these universal pathways remain mysterious. Here, we provide the first investigation of RFC1 gene function in vivo using zebrafish. We showed that RFC1 is expressed in neural progenitor cells within the developing cerebellum, where it maintains their genomic integrity during neurogenic maturation. Accordingly, RFC1 loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data point to a specific role of RFC1 in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlying RFC1-related disorders.