Zebrafish Hearing-Related Disease Models

Zebrafish Hearing-Related Disease Models

Hearing loss is an extremely common disorder, the incidence of which increases with age. Although environmental contributions such as noise and drug exposures are long-recognized risk factors, genetic susceptibility to hearing loss is considered to be responsible for over half of diagnoses. Particularly in developed countries, about 80% of congenital hearing loss is due to genetic causes and the remaining fraction is attributed to environmental factors. Approximately 2 of 3 genetic hearing loss conditions are nonsyndromic. According to the Hereditary Hearing loss website, there are over 100 genes associated with nonsyndromic hearing loss. Of the nonsyndromic deafness cases, 70% are classified as autosomal recessive deafness (DFNB) and 20% as autosomal dominant deafness (DFNA). The remaining cases are caused by X-linked or mitochondrial genetic mutations. In syndromic deafness, hearing loss is usually associated with other clinical manifestations such as blindness or dysmorphic craniofacial features.

Like most fish, zebrafish have two related sensory organs that use the mechanosensory hair cell receptors: (1) the inner ear similar to mammalian ears used to detect sound, motion, and gravity, and (2) the lateral line, a fish- and amphibian-specific organ used to detect water flow over the surface of the body. Recently, zebrafish have been increasingly used as a model for human disease, including human deafness, because its genome has been fully sequenced, and targeted gene inactivation has become commonplace. Zebrafish models of hair cell dysfunction exhibit easily scorable behavioral traits, providing an accessible and reproducible approach to evaluate the loss of function. Zebrafish are also advantageous in terms of visualizing defects in the inner ear as their eggs are fertilized externally and the larvae are optically transparent for the first several days of development, enabling direct observation of the sensory epithelium of the inner ear.

The inner ear and the lateral line in zebrafish.

Figure 1. The inner ear and the lateral line in zebrafish. (Varshney G K, et al. 2016)

Our Zebrafish Models of Hearing-Related Disease

Creative Biogene, a zebrafish preclinical contract research organization, offers a suite of zebrafish hearing-related disease models that be used to understand the molecular and cellular basis of the disease, assess the functional role of human genetic variations, and screen potential compounds for liver disease therapy. We can conduct high throughput forward genetic screens and chemical screens in zebrafish to identify new therapeutic targets and treatments. Currently, several large-scale mutagenesis screens have identified multiple genes essential for balance and hearing in zebrafish.

Three different approaches are used to construct zebrafish hearing-related disease models:

  • Random mutagenesis approaches: chemical mutagenesis using N-ethyl-Nnitrosourea (ENU) as a mutagen
  • Targeted mutagenesis approaches: including Zinc Finger Nucleases (ZFNs), TALENs, and CRISPR/Cas9
  • Morpholino-mediated knockdown of mRNA

So far, Creative Biogene has developed a variety of zebrafish hearing-related disease models, including but not limited to:

  • Sensorineural syndromic deafness models
    1) Branchiootorenal/Branchiootic syndrome
    2) Waardenburg syndrome types IIE (WS2E) and IV (WS4)
  • Nonsyndromic deafness models
    1) Epithelial integrity
    2) Sensory organ architectural defects
    3) Hair cell dysfunction

Our zebrafish models provide a strong experimental platform for testing and validating candidate genes implicated in otic pathologies. Contact us to learn more about our zebrafish hearing-related disease model services.

References

  • Vona B, et al. Small fish, big prospects: using zebrafish to unravel the mechanisms of hereditary hearing loss. Hearing Research, 2020: 107906.
  • Varshney G K, et al. Using zebrafish to study human deafness and hearing regeneration. Genetics of Deafness. Karger Publishers, 2016, 20: 110-131.
  • Blanco-Sánchez B, et al. Zebrafish models of human eye and inner ear diseases. Methods in cell biology. Academic Press, 2017, 138: 415-467.

For research use only. Not intended for any clinical use.

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