Sensory hair cell (HC) damages are usually responsible for sensorineural hearing loss (Wagner and Shin, 2019; Guo et al., 2021). This process can be caused by multiple factors including genetic alterations, noise, ototoxic drugs, aging, etc (Wagner and Shin, 2019; Guo et al., 2021). Hearing loss is becoming a global health problem and hereditary hearing loss caused by deafness gene mutations accounts for 80%. Therefore, it is vital to identify the newly critical deafness genes and elucidate the regulators of auditory organ development. Until now, more than 120 deafness genes have been identified (https://hereditaryhearingloss.org), and there are many other genes were shown to be linked to hearing loss in recent years (Zhu et al., 2018; Liu, Y. et al., 2019; Cui et al., 2020; de Bruijn et al., 2020; Mutai et al., 2020; Qian et al., 2020; Zhang et al., 2020; Cheng et al., 2021; da Silva et al., 2021; Fu et al., 2021; Vona et al., 2021; Cheng et al., 2022; Hong et al., 2022; Zhang et al., 2022). Exploring the function of deafness genes is dependent on the construction of the animal model. Established model organisms, such as chicks, zebrafish, mice, and rats, have been widely used in auditory research (Kondo et al., 2002; Burns and Stone, 2017; Wei et al., 2022). Mammals are commonly thought to be superior to non-mammalian vertebrates as hearing models because of having cochlear structure and relatedness more closely to humans (Wei et al., 2022). While, the limitations of them are also obvious containing complicated anatomic separation of the cochlea, time-consuming phenotype readouts of HC, high cost and low throughput, etc (Domarecka et al., 2020). Characteristics of high fecundity, transparency, easy visualization, and genetic manipulation make zebrafish an economic and attractive model organism for rapid deafness gene identification and auditory studies (Yao et al., 2016; Burns and Stone, 2017; Domarecka et al., 2020).

Zebrafish HCs are distributed at mechanosensory organs that detect sound and motion, involved in the otic vesicle located in the head and the lateral line (LL) system. The otic vesicle is mainly comprised of three orthogonally arranged semicircular canals, utricles, and saccules (Whitfield et al., 2002). The three typical HC clusters vertically inserted into the ampulla, known as crista HCs, can convert external vibrating stimuli to electrophysiological signals transmitted by the nervous system (Whitfield et al., 2002). Moreover, the LL system, another important sensory organ, is composed of a series of regularly aligned neuromasts where HCs are surrounded by supporting cells and mantle cells (Thomas et al., 2015). Neuromast is the basic functional unit of LL characterized by being positioned at the surficial body and easy to staining and imaging (Thomas et al., 2015). Lots of researchers have devoted themselves to exploring the molecular mechanism regarding HC development and regeneration. It has been reported that Wnt, Notch, and Fgf signaling pathways, some transcription factors (Atoh1, Sox2, Math1, Gata3), as well as newly found microRNA are widely involved in these processes (Groves et al., 2013). More than 120 non-syndromic hearing loss genes have been identified, however, there are still many deafness genes waiting to be discovered.

Tripartite motif (TRIM) proteins, also called RBCC proteins, are comprised of a RING domain, one or two B-boxes, and a predicted coiled-coil region where generally followed by highly variable C-terminal domains like B30.2 domain (PRY-SPRY) (Nisole et al., 2005; McNab et al., 2011). As a kind of E3 ubiquitin ligases, they are widely implicated in multiple biological processes, including cell proliferation, cell differentiation, apoptosis, cell-cycle regulation, and antiviral innate immune responses (Nisole et al., 2005; McNab et al., 2011). Ftr82 belongs to a large new subset of TRIM genes termed fish novel TRIM (finTRIM, ftr) exclusively in teleost fish and the closest mammalian relatives are trim16 and trim25 but are not true orthologs (Chang et al., 2017; Luo et al., 2017; Langevin et al., 2019). Limited studies showed that the finTRIM genes were mainly related to innate immunity against viral infection (Langevin et al., 2017; Chen et al., 2019; Liu, W. et al., 2019; Lv et al., 2019; Wu et al., 2019). Research indicated that ftr36 can trigger IFN pathway and mediate the inhibition of viral replication (Chen et al., 2019). Overexpression of FTR83 induces IFN upregulation and inhibits RNA virus infections like IHNV, VHSV, and SVCV (Langevin et al., 2017). The limited studies of ftr82 suggest that overexpression of FTR82 does not induce upregulation of IFN and neither exhibits antiviral activity in zebrafish (Langevin et al., 2017). While in orange spotted grouper, ftr82 negatively regulates IFN response and enhances viral particle replication of SGIV and RGNNV (Lv et al., 2019). In addition, a publication identifies ftr82 as a vascular gene that plays an important role in vascular development in zebrafish (Chang et al., 2017). Furthermore, ftr82 is specifically expressed in the otic vesicles of early-phase zebrafish embryos (Kudoh et al., 2001; Thisse et al., 2001). It can be seen that the function of the ftr82 gene remains largely unknown and neither related description of TRIM proteins in auditory research.

Here, we investigated the role of ftr82 in HC development and hearing function using the zebrafish model. Whole-mount in situ hybridization (WISH) was performed to characterize the expression profile of ftr82 in detail and specific expression in HCs of otic vesicle was observed. Loss of function experiments by either morpholino injection or CRISPR-Cas9 could induce the defects of crista HCs and neuromasts in morphology and function. Knockdown or knockout of ftr82 both caused defective startle response. Treatments with co-injection of exogenous ftr82 mRNA could rescue the related phenotypic changes. Moreover, hair cell apoptosis signaling was detected in deficiency of ftr82, which largely explained the phenotype of HC loss. In summary, our study reveals that ftr82 plays important roles in HC development and auditory function in zebrafish. This work not only helps us to comprehensively understand the gene function of ftr82 but also provides new insight into the identification of potential deafness genes.