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Myosin XVA: dancing at the tips of the stereocilia

Du, Haiboa; Li, Nanaa; Xu, Zhiganga,b,∗

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Journal of Bio-X Research: June 2020 - Volume 3 - Issue 2 - p 60-65
doi: 10.1097/JBR.0000000000000060
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The actin cytoskeleton plays important roles in various cell structures and activities. The formation and function of the actin cytoskeleton require the actin-based motors, myosins, which comprise a large superfamily of adenosine triphosphatases (ATPases). Utilizing the energy released from ATP hydrolysis, myosins move along actin filaments to generate motility or force.[1] Each myosin contains a highly conserved N-terminal motor (or head) domain, a central neck domain and a C-terminal tail region. The motor domain contains ATPase activity that catalyzes ATP hydrolysis and regulates actin-binding. The neck domain binds light chains or calmodulins, and acts as a lever arm for force transduction. The C-terminal tail region is the most divergent among the different myosins and contains various domains that mediate oligomerization or cargo interactions.

Myosins form a large and diverse protein superfamily, whose members are grouped into more than 30 distinct classes.[2] Myosin II (MYO2), the first myosin discovered, is designated as a “conventional myosin”, and the other myosins are considered as “unconventional myosins”. The conventional myosin is found in muscle cells and the contractile ring in non-muscle cells, forming bipolar thick filaments via tail-mediated oligomerization that pull actin filaments to produce contraction.[3] The unconventional myosins, however, do not form bipolar thick filaments. Instead, their tails mediate binding to the plasma membrane or cargo proteins.[4] The unconventional myosins are implicated in diverse cellular processes, such as organelle trafficking, F-actin organization and cell movement, among others.[5]

Myosin tail homology 4 - protein 4.1, ezrin, radixin, and moesin (MyTH4-FERM) myosins are a group of unconventional myosins involved in actin-based finger-like protrusions such as filopodia, microvilli, and stereocilia.[6] Known MyTH4-FERM myosins include MYO7A, MYO7B, MYO10, and MYO15A, all of which contain the MyTH4-FERM domain in their C-terminal tail regions (Fig. 1). The MyTH4 and FERM domains form a structural and functional supramodule, the MyTH4 domain mediating microtubule binding and the FERM domain mediating cargo interactions.[7–9] MYO10 has one MyTH4-FERM domain after a single α-helix (SAH) domain, a proline, glutamate, serine, threonine peptide (PEST) sequence and several Pleckstrin homology (PH) domains. MYO7A, MYO7B, and MYO15A have 2 tandem MyTH4-FERM domains separated by an SRC homology 3 (SH3) domain. MYO15A also contains a PDZ-binding interface (PBI) at the C-terminal end that mediates interaction with the PDZ (PSD95, Dlg1, and ZO-1) domain.

Figure 1
Figure 1:
Schematic structure of MyTH4-FERM myosins. FERM = protein 4.1, ezrin, radixin, and moesin, IQ = calcium or light-chain binding sites, Motor = motor domain, MyTH4 = myosin tail homology 4, PBI = PDZ-binding interface, PEST = proline, glutamate, serine, threonine peptide, PH = pleckstrin homology, SAH = single α-helix, SH3 = SRC homology 3.

In this review, we will focus on the unconventional myosin MYO15A. MYO15A is localized at the tips of stereocilia in inner ear hair cells and plays important roles in development and maintenance of stereocilia. We will discuss the expression pattern of the MYO15A gene in the inner ear, the biochemical properties of the MYO15A protein, the association of MYO15A mutations with hearing loss and our present understanding of how MYO15A regulates stereocilia development and maintenance.

Database Search Strategy

An electronic search of the PubMed database was performed to identify relevant publications from 1945 to 2019 using the following “myosin 15A” OR “myosin XVA” OR “myo15a”. The results were further screened by title and abstract to only present studies describing the expression; properties; interactions; or functions of MYO15A. Lastly, the authors screened the reference list of included publications to identify other potentially relevant publications.

MYO15A/Myo15a gene expression

Both human MYO15A and mouse Myo15a genes contain 66 exons, encoding a large protein of up to nearly 400 kDa.[10] Exon 2 of the MYO15A/Myo15a gene is subjected to alternative splicing, which gives rise to MYO15A isoforms of different lengths.[10] The short MYO15A isoform (MYO15A-S) contains a N-terminal motor domain, a central neck domain and a C-terminal tail region. The long MYO15A isoform (MYO15A-L) has an additional large N-terminal extension of unknown function before the motor domain (Fig. 1). Moreover, alternative splicing was observed in exons 8 and 26, which are 6 nucleotides (nt) and 216 nt/189 nt (human/mouse) long, respectively.[10] Inclusion of exon 8 affects the motor domain, while inclusion of exon 26 affects the neck domain, whose biological significance remains undefined.

In situ hybridization using a probe for both long and short isoforms showed that Myo15a transcripts are first expressed in the developing inner ear at embryonic day 13.5 (E13.5).[11] At E17.5, Myo15a expression is restricted to the sensory epithelium in both the vestibula and the cochlea. At postnatal day 8 (P8), Myo15a transcripts are only detected in the hair cells but not in the supporting cells. Similar results were obtained when a long isoform-specific probe was used.[11] The specific expression pattern of Myo15a transcripts in the inner ear, especially in the hair cells, suggests that MYO15A might play important roles in the development and/or function of the hair cells.

Furthermore, quantitative PCR (qPCR) showed that Myo15a transcripts exhibit isoform switching during development in the mouse cochlea.[12]Myo15a-l transcripts become progressively more abundant during development, increasing about 9-fold from P0 to P21. In contrast, expression of Myo15a-s transcripts is significantly decreased about 21-fold from P0 to P6. Meanwhile, the total amount of Myo15a transcripts remains stable during development. The developmentally isoform switching suggests that the different MYO15A isoforms play different roles in the hair cells.

Biochemical properties of MYO15A protein

The biochemical properties of MYO15A have been investigated using its purified motor domain plus the neck region. The results showed that MYO15A is a plus end-directed myosin that moves rapidly along the actin filaments.[13] The duty ratio is an important property for myosins, defined as the fraction of the ATPase cycle that myosin spends strongly associated with F-actin. MYO15A is a high-duty ratio motor, suggesting that it can move along F-actin processively.[13] In vitro experiments also showed that heat shock protein 90 (HSP90) and its co-chaperone UNC-45B could bind to MYO15A and promote its folding.[13]

The neck region of MYO15A contains 3 predicted light-chain binding sites (IQ motifs). The first and second IQ motifs bind to regulatory light chain (RLC) and essential light chain (ELC), respectively, while the third IQ motif seems to be unoccupied.[13] Calmodulin could compete with ELC for binding to the second IQ motif, although with low affinity.[13] MYO15A does not have a predicted coiled-coil sequence and, at present, it is unknown whether it could dimerize in vivo.

The C-terminal tail of MYO15A contains two tandem MyTH4-FERM domains separated by an SH3 domain, as well as a PBI at the C-terminal end. It has been suggested that MYO15A binds to the C terminus of the actin-regulatory protein, epidermal growth factor receptor kinase substrate 8 (EPS8), possibly via its MyTH4-FERM domain.[14] MYO15A also binds to the PDZ domains of scaffold protein whirlin (WHRN) via its C-terminal MyTH4-FERM and PBI.[15,16] In summary, MYO15A is a plus end-directed, high-duty ratio motor, and interacts with RLC, ELC, calmodulin, EPS8, and WHRN via its multiple domains. Mutations that affect these domains destroy the function of MYO15A and lead to hearing loss, which will be discussed in the next section.

Mutations in the MYO15A/Myo15a gene cause hearing loss in humans and rodents

In 1993, the gene associated with congenital, recessive deafness DFNB3 was mapped to the pericentromeric region of chromosome 17, which was subsequently refined to 17p11.2.[17,18] In 1998, mutations in the human MYO15A gene were identified as responsible for DFNB3.[19] Since then, more than 70 mutations in MYO15A gene have been identified in patients with hearing loss (Fig. 2).[20–44] These mutations cover the full length of MYO15A, affecting every important domain and motif.

Figure 2
Figure 2:
MYO15A/Myo15a mutations associated with hearing loss in human (above) and rodents (below). FERM = protein 4.1, ezrin, radixin, and moesin, IQ = calcium or light-chain binding sites, Motor = motor domain, MyTH4 = myosin tail homology 4, PBI = PDZ-binding interface, SH3 = SRC homology 3.

Animal models containing Myo15a gene mutations have also been identified. Shaker-2 (sh2) is a recessive mouse mutant with hearing and balancing problems and has been suggested as the mouse model of DFNB3.[17] In 1998, mutation in the Myo15a gene was identified as responsible for the phenotypes in sh2 mice.[45,46] Another mouse line, shaker-2j (sh2j), has similar phenotypes as sh2, and mutation in the Myo15a gene was identified as the causative gene.[11] The mutations in sh2 and sh2j mice affect the motor and tail domains of MYO15A, respectively, suggesting that both regions are critical for the function of MYO15A in hair cells. A deletion in the Myo15a gene that encodes part of the motor domain was then identified in the spontaneous deaf kuru2 mice.[47] Recently, a knock-in mouse line was established by introducing an E1086X nonsense mutation into the Myo15a gene, mimicking the E1105X mutation in DFNB3 patients.[12,21] Because this mutation lies in exon 2, it only affects MYO15A-L, but leaves MYO15A-S unaffected. The resultant Myo15aΔN/ΔN mice show less severe hearing loss compared with sh2 or sh2j mice and normal vestibular function.[12] Lastly, a spontaneous mutation L3157P in the second MyTH4 domain of MYO15A was identified in the circling-2 (ci2) rats that possess hearing, balancing, and vision deficits.[48] These animal models provide valuable tools for the investigation into the function of MYO15A in hearing.

MYO15A regulates the development and maintenance of stereocilia

Immunostaining with an antibody against common epitopes present in both isoforms, PB48, showed that MYO15A is localized at the tips of all stereocilia in both OHCs and IHCs (Fig. 3A and B).[12,49] MYO15A immunoreactivity was first detected at the stereociliary tips of mouse E14.5 vestibular hair cells and E18.5 cochlear hair cells, coinciding with the onset of the staircase architecture formation of the stereocilia.[12] The two known MYO15A binding partners, EPS8 and WHRN, are also localized at the tips of stereocilia.[14–16] MYO15A, EPS8, and WHRN form a tripartite complex at the tips of stereocilia and regulate stereocilia elongation. The same antibody, PB48, was also used in immunostaining of Myo15a△N/△N mice that lack MYO15A-L, which revealed that MYO15A-S is localized at the tips of the tallest row stereocilia in both OHCs and IHCs (Fig. 3C and D).[12] The localization of MYO15A-L was examined by performing immunostaining of normal control mice with PB888, an antibody specific to the N-terminal extension part. The results suggested that MYO15A-L is localized at the tips of the shorter row stereocilia in IHCs but at the tips of all stereocilia in OHCs (Fig. 3E and F).[12]

Figure 3
Figure 3:
MYO15A localization at the tips of stereocilia. (A–F) MYO15A immunoreactivity was examined in mice of different genotypes (+/+, +/ΔN or ΔN/ΔN) and ages (P7 or P14) as indicated. Adapted from Fang et al.[12] PB48 is an antibody that recognizes both MYO15A isoforms, and PB888 is an antibody specific to MYO15A-L. Scale bars: 5 μm. (G, H) Schematic illustrations showing the localization of different MYO15A isoforms in the stereocilia. IHC = inner hair cell, Iso 1 = isoform 1 (MYO15A-L), Iso 2 = isoform 2 (MYO15A-S), OHC = outer hair cell, P7 = postnatal day 7, P14 = postnatal day 14.

The role of MYO15A in the development and/or maintenance of stereocilia was further investigated using Myo15a mutant mice. In sh2/sh2 or sh2j/sh2j mice that lack both functional MYO15A isoforms, the stereocilia of cochlear and vestibular hair cells are extremely short.[11,45] Hair bundles in their IHCs also show supernumerary stereocilia rows.[12] Similar stereocilia abnormalities were also observed in Whrn- or Eps8-deficient mice.[14,50] However, overexpressed MYO15A-S in normal control hair cells has no effect on the elongation of developing stereocilia.[49] Interestingly, the effect of Myo15a disruption on stereocilia development differs between IHCs and OHCs. In sh2/sh2 IHCs, all the stereocilia are equally short, and no obliquely oriented tip-links are observed. However, the short stereocilia of sh2/sh2 OHCs still retain a staircase arrangement with prominent tip-links. It has also been shown that fast adaptation and Ca2+ sensitivity of mechanical-electrical transduction (MET) are affected in IHCs but not OHCs of sh2/sh2 mice.[51]

In the Myo15a△N/△N mice that lack MYO15A-L, the development of the staircase architecture of stereocilia is unaffected by P10, suggesting that MYO15A-L is not required for stereocilia development.[12] However, from P32 onwards in Myo15a△N/△N hair cells, the second row stereocilia are significantly shorter, and the third row stereocilia are almost completely resorbed, whereas the tallest row stereocilia are largely unaffected, suggesting that MYO15A-L is indispensable for the postnatal maintenance of the shorter row stereocilia.[12] Further examination of the ultrastructure of Myo15a△N/△N shorter row stereocilia at P8 revealed exaggerated and over-elongated prolate tips filled with actin filaments, suggesting that actin polymerization was dysregulated at this position.[12] It is worth noticing that the localization of WHRN and EPS8 is unaffected in the Myo15a△N/△N mice, suggesting that MYO15A-S is sufficient to traffic these two proteins to the tips of stereocilia.[12] The sensitivity of MET was also affected in the Myo15a△N/△N IHCs but not OHCs.[12] In summary, the present data suggest that MYO15A-S and MYO15A-L are localized at the tips of stereocilia of different rows, and play different but important roles in the development and maintenance of stereocilia (Fig. 3G and H).

Conclusion and perspectives

Research over the last 2 decades suggest that the unconventional myosin MYO15A is localized at the tips of stereocilia and regulates stereocilia development/maintenance. The MYO15A gene is subjected to alternative splicing, which gives rise to different MYO15A isoforms with slightly different localization and functions. MYO15A-S is localized at the tips of the tallest row stereocilia and is necessary for early stereocilia development. However, MYO15A-L is localized at the tips of the shorter row stereocilia in IHCs, and is indispensable for the postnatal maintenance of the shorter row stereocilia. At present it remains unclear how the different localization and function of the 2 MYO15A isoforms are regulated. The N-terminal extension part that is unique to MYO15A-L must be important for this discrepancy. Therefore, identification of proteins that specifically bind to this N-terminal extension will certainly help answer this question.

At the tips of the tallest row stereocilia, MYO15A-S interacts with WHRN and EPS8, forming a so-called stereocilia tip complex. This complex also contains other components such as GPSM2 and Gαi3.[52,53] There is evidence suggesting that MYO15A-EPS8 forms the core of this complex and is transported to the stereocilia tips first, then WHRN-GPSM2-Gαi3 is added to the pre-existing MYO15A-EPS8 stereocilia tip complex.[53] Mutations that affect any component in this complex cause similar stereocilia elongation phenotypes, further supporting the role of this complex in stereocilia development. At present how this complex regulates the length of the stereocilia is still unknown and awaits further investigation.

MYO15A-L is localized at the tips of shorter row stereocilia in IHCs, where actin capping protein subunit B2 (CAPZB2), twinfilin 2 (TWF2) and EPS8-like 2 (EPS8L2) also reside.[54–57] Mice lacking CAPZB2 or EPS8L2 show stereocilia maintenance abnormality similar to that observed in Myo15a△N/△N mice.[56,57] At present it is unknown whether all these proteins can bind to each other and form a protein complex, although CAPZB2 has been shown to bind TWF2.[57] The MET complex also localizes at the tips of shorter stereocilia, near the lower end of tip links.[58–62] It remains to be tested whether these proteins have connections with the MET complex. However, the normal amplitude of MET currents in Myo15a or Eps8l2 mutant mice suggests that neither MYO15A nor EPS8L2 plays an indispensable role in MET.[12,51,56] Further investigations are warranted to learn more about all these proteins localized at the tips of shorter stereocilia.

Different expression patterns and roles of MYO15A isoforms in the stereocilia suggest different intervention strategies for patients with different MYO15A mutations. Adeno-associated viruses were proven to efficiently deliver genes into inner ear cells.[63–65] This approach has been successfully applied in the treatment of hearing loss in several mouse models.[66–71] Furthermore, the powerful gene editing techniques provide a promising therapeutic strategy towards hearing loss.[72,73] Recently this strategy was employed to successfully improve the auditory function of the Tmc1 mutant deaf mice.[74,75] For the potential treatment of MYO15A-related hearing loss, a bacterial artificial chromosome containing full-length Myo15a gene has been shown to rescue the deafness phenotype in sh2 mice.[45] Compared to MYO15A-S, MYO15A-L is not required for the stereocilia until a later developmental stage, which gives patients with mutations in MYO15A exon 2 a broader time window for intervention. Further investigations into the function and regulation of MYO15A will certainly help to develop more efficient treatments of related patients.



Author contributions

HD, NL and ZX retrieved the literature and wrote the manuscript. All the authors approved the final version of the paper.

Financial support

Our laboratory is supported by the National Key Basic Research Program of China (No. 2018YFC1003600), the National Natural Science Foundation of China (No. 81771001), Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology (No. SPKLACDB-2019000), and the Fundamental Research Funds of Shandong University (No. 2018JC025).

Conflicts of interest

The authors declare that they have no conflicts of interest.


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hair cells; inner ear; MYO15A; myosins; stereocilia

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