How Zebrafish Can Drive the Future of Genetic-based Hearing and Balance Research

Abstract

Over the last several decades, studies in humans and animal models have successfully identified numerous molecules required for hearing and balance. Many of these studies relied on unbiased forward genetic screens based on behavior or morphology to identify these molecules. Alongside forward genetic screens, reverse genetics has further driven the exploration of candidate molecules. This review provides an overview of the genetic studies that have established zebrafish as a genetic model for hearing and balance research. Further, we discuss how the unique advantages of zebrafish can be leveraged in future genetic studies. We explore strategies to design novel forward genetic screens based on morphological alterations using transgenic lines or behavioral changes following mechanical or acoustic damage. We also outline how recent advances in CRISPR-Cas9 can be applied to perform reverse genetic screens to validate large sequencing datasets. Overall, this review describes how future genetic studies in zebrafish can continue to advance our understanding of inherited and acquired hearing and balance disorders.

The effect of time regime in noise exposure on the auditory system and behavioural stress in the zebrafish

“…The zebrafish Danio rerio (Cyprinidae) is an otophysian species, which possess Weberian ossicles that link the swim bladder to the inner ear enhancing auditory sensitivity especially at higher frequencies 23 . Although zebrafish has become a well-established model in hearing research to investigate inner ear development and ototoxicity 24 , 25 , there is scarce information on how the acoustic environment can affect its hearing sense 26 . Previously, we reported NIHL and associated hair cell loss with continuous noise exposure in adult zebrafish 27 , but whether specific time regimes in noise exposure result in different auditory effects and the underlying pathological mechanisms remain to be investigated.…”

The Cholinergic Lateral Line Efferent Synapse: Structural, Functional and Molecular Similarities With Those of the Cochlea

“…Moreover, zebrafish is amenable to rapid transgenic modification to express tissue specific transgenes encoding fluorescent markers or gene products ( Kwan et al, 2007 ). This is especially useful in the transparent larvae where HC structure can easily be visualized in vivo and dynamic cellular processes can be imaged in a live, intact preparation ( Esterberg et al, 2014 ; Graydon et al, 2017 ; Pickett et al, 2018 ; Zhang et al, 2018 ; Wong et al, 2019 ; Holmgren and Sheets, 2021 ; Sheets et al, 2021 ).…”

“…Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of HC biology, including mechanotransduction and synaptic physiology ( Kindt and Sheets, 2018 ), as well as mechanisms of both hereditary and acquired HC dysfunction ( Nicolson, 2005 ; Sheets et al, 2021 ). However, with the rise of the zebrafish LL as a model in which to study auditory system function and disease, there has been an increased interest in studying its efferent system and evaluate the similarity between mammalian and piscine efferent synapses.…”

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

“…To study the energy demands and metabolic impact of hair-cell neurotransmission we examined hair cells in the lateral line of larval zebrafish ( Figure 1A–C ). Zebrafish allow us to study hair cells that are genetically, functionally, and morphologically similar to mammalian hair cells in vivo ( Sheets et al, 2021 ). For example, in both zebrafish and mammals, Ca v 1.3 calcium channels and Otoferlin are essential for proper hair-cell function ( Figure 1D–D’ ; Brandt et al, 2003 ; Chatterjee et al, 2015 ; Roux et al, 2006 ; Sidi et al, 2004 ).…”