Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Lelli, Andrea; Michel, Vincent; Monvel, Jacques Boutet de; Cortese, Matteo; Grau, Montserrat Bosch; Aghaie, Asadollah; Perfettini, Isabelle; Dupont, Typhaine; Avan, Paul; El-Amraoui, Aziz; Petit, Christine

doi:10.1085/jgp.1472oia7

Cited by 9 publications

(16 citation statements)

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“…Some mutations in DIAPH1 correlate with hearing loss and there are some evidence of formin involvement in formation of stereocilia in specialized inner ear cells (Neuhaus et al, 2017;Ueyama et al, 2016). At the same time, the formation and function of these same structures are dependent on a variety of myosin isoforms, including myosin 1C (Stauffer et al, 2005), myosins 3a and b (Lelli et al, 2016), myosin 6 (Hertzano et al, 2008;Seiler et al, 2004), myosins 7a (Morgan et al, 2016;Yu et al, 2017), and myosin 15 (Anderson et al, 2000;Friedman et al, 1999). Formation and maintenance of integrity of actin bundles (radial/dorsal fibers, transverse arcs and ventral stress fibers) depend on formins (Hotulainen and Lappalainen, 2006;Oakes et al, 2012;Schulze et al, 2014), but these structures depend also on myosin 2 driven force generation, and nonmuscle myosin 2 paralogs are components of some of these structures (Beach et al, 2014;Hu et al, 2017;Kuragano et al, 2018;Shutova et al, 2017;Vicente-Manzanares et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

The formin inhibitor SMIFH2 inhibits members of the myosin superfamily

Nishimura

Shi

Zhang

et al. 2021

Journal of Cell Science

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The small molecular inhibitor of formin FH2 domains, SMIFH2, is widely used in cell biological studies. It inhibits formin-driven actin polymerization in vitro, but not polymerization of pure actin. It is active against several types of formins from different species (Rizvi et al., 2009). Here, we found that SMIFH2 inhibits retrograde flow of myosin 2 filaments and contraction of stress fibers. We further checked the effect of SMIFH2 on non-muscle myosin 2A and skeletal muscle myosin 2 in vitro and found that SMIFH2 inhibits myosin ATPase activity and ability to translocate actin filaments in the in vitro motility assay. The inhibition of non-muscle myosin 2A in vitro required a higher concentration of SMIFH2 than for the inhibition of retrograde flow and stress fiber contraction in cells. We also found that SMIFH2 inhibits several other non-muscle myosin types, e.g. mammalian myosin 10, Drosophila myosin 7a and Drosophila myosin 5, more efficient than inhibition of formins. These off-target inhibitions demand additional careful analysis in each case when solely SMIFH2 is used to probe formin functions.

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Section: Discussionmentioning

confidence: 99%

The formin inhibitor SMIFH2 inhibits members of the myosin superfamily

Nishimura

Shi

Zhang

et al. 2021

Journal of Cell Science

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“…How the bundle adopts its staircase pattern, however, remains largely unclear. Resident bundle proteins such as Myo15a and Myo3a, and their cargo delivered to stereocilia tips, are required to various extents for graded heights and concurrent graded amounts of some proteins at tips across rows (Belyantseva et al, 2003(Belyantseva et al, , 2005Ebrahim et al, 2016;Lelli et al, 2016;Manor et al, 2011;Mburu et al, 2003;Probst et al, 1998;Salles et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

A link between planar polarity and staircase-like bundle architecture in hair cells

et al. 2016

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Sensory perception in the inner ear relies on the hair bundle, the highly polarized brush of movement detectors that crowns hair cells. We previously showed that, in the mouse cochlea, the edge of the forming bundle is defined by the 'bare zone', a microvilli-free sub-region of apical membrane specified by the Insc-LGN-Gαi protein complex. We now report that LGN and Gαi also occupy the very tip of stereocilia that directly abut the bare zone. We demonstrate that LGN and Gαi are both essential for promoting the elongation and differential identity of stereocilia across rows. Interestingly, we also reveal that total LGN-Gαi protein amounts are actively balanced between the bare zone and stereocilia tips, suggesting that early planar asymmetry of protein enrichment at the bare zone confers adjacent stereocilia their tallest identity. We propose that LGN and Gαi participate in a long-inferred signal that originates outside the bundle to model its staircase-like architecture, a property that is essential for direction sensitivity to mechanical deflection and hearing.

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“…Mutations in MYO3A underlie both dominant- and recessive forms of human hearing loss, DFNA73 and DFNB30 respectively 29; 30 . Furthermore, Myo3a -/- Myo3b -/- double knockout mice are profoundly deaf 31 . Two suggestive associations are downstream of genes that were previously identified as being associated with self-reported hearing difficulty in the UKBB cohort 22 , ARID5B and ZNF318 although the lead SNPs associated with the two traits are different in both cases (see Table 3 and Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in RCOR1 is associated with tinnitus in UK Biobank

Wells

Abidin

Фрейдин

et al. 2020

Preprint

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Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. We performed a case-control genome-wide association study for self-reported tinnitus in 172,608 UK Biobank volunteers. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p=1.7E-08), rs4900545 (p=1.8E-08) and 14:103042287_CT_C (p=3.50E-08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p<1E-06.

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Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Cited by 9 publications

References 50 publications

The formin inhibitor SMIFH2 inhibits members of the myosin superfamily

The formin inhibitor SMIFH2 inhibits members of the myosin superfamily

A link between planar polarity and staircase-like bundle architecture in hair cells

Genetic variation in RCOR1 is associated with tinnitus in UK Biobank

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