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<p>With orthologs for &gt;70% of human genes, zebrafish represent a popular model for investigating development and disease, particularly when murine models are unsuitable. One caveat of zebrafish genetic models is the prevalence of paralogs, where compensation and transcriptional adaptation can complicate our understanding. Usher syndrome type 1 F (USH1F), caused by <i>PCDH15</i> mutations, exemplifies the need for alternatives models; the primary site of injury, calyceal processes (CP), are uniquely lacking from photoreceptors of nocturnal rodents. Here we demonstrate that contrary to previous reports, zebrafish <i>pcdh15a/b</i> paralogs are not absolutely restricted to ear and eye tissues respectively. Instead, both paralogs are expressed and required in the mechanosensitive hair cells and retinal photoreceptors. Double mutants present the most severe phenotypes: loss of kinocilial and stereocilial links in the ear, and disorganization of CPs, inner/outer segment detachment, and photoreceptor cell death. We also demonstrate that ear and eye-specific phenotypes may be isolated via isoform-specific knockout. These data highlight the strengths of zebrafish to study pathomechanism in vivo. They should also caution researchers from defining paralogs as discrete, absolutely restricted functional units without exceptional evidence. When possible, double mutants may be preferable for studying gene function, and modelling diseases where humans have a single ortholog.</p>

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Overlapping expression and co-operative function of the zebrafish pcdh15 paralogs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Paul W. Chrystal,
  • Lisa Kuzmanova,
  • Jingpin Liu,
  • Alexa Izvorean,
  • Ishmael Majeed,
  • Jefferson F. Tjoenardi,
  • Qian Lin,
  • Vincent Tropepe

摘要

With orthologs for >70% of human genes, zebrafish represent a popular model for investigating development and disease, particularly when murine models are unsuitable. One caveat of zebrafish genetic models is the prevalence of paralogs, where compensation and transcriptional adaptation can complicate our understanding. Usher syndrome type 1 F (USH1F), caused by PCDH15 mutations, exemplifies the need for alternatives models; the primary site of injury, calyceal processes (CP), are uniquely lacking from photoreceptors of nocturnal rodents. Here we demonstrate that contrary to previous reports, zebrafish pcdh15a/b paralogs are not absolutely restricted to ear and eye tissues respectively. Instead, both paralogs are expressed and required in the mechanosensitive hair cells and retinal photoreceptors. Double mutants present the most severe phenotypes: loss of kinocilial and stereocilial links in the ear, and disorganization of CPs, inner/outer segment detachment, and photoreceptor cell death. We also demonstrate that ear and eye-specific phenotypes may be isolated via isoform-specific knockout. These data highlight the strengths of zebrafish to study pathomechanism in vivo. They should also caution researchers from defining paralogs as discrete, absolutely restricted functional units without exceptional evidence. When possible, double mutants may be preferable for studying gene function, and modelling diseases where humans have a single ortholog.