No abstract

Defects of CIB2, calcium‐ and integrin‐binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type‐IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2 −/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2 −/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair‐cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2 −/− mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

Analysis of mice deficient for myosin IIIa and myosin IIIb shows that class III myosins limit the elongation of stereocilia and of subsequently regressing microvilli, thus contributing to the early hair bundle shaping.

Mutations in the myosin VIIa gene cause Usher syndrome type IB (USH1B), characterized by deaf-blindness. A delay of opsin trafficking has been observed in the retinal photoreceptor cells of myosin VIIa-deficient mice. We identified spectrin βV, the mammalian β-heavy spectrin, as a myosin VIIa- and rhodopsin-interacting partner in photoreceptor cells. Spectrin βV displays a polarized distribution from the Golgi apparatus to the base of the outer segment, which, unlike that of other β spectrins, matches the trafficking route of opsin and other phototransduction proteins. Formation of spectrin βV-rhodopsin complex could be detected in the differentiating photoreceptors as soon as their outer segment emerges. A failure of the spectrin βV-mediated coupling between myosin VIIa and opsin molecules thus probably accounts for the opsin transport delay in myosin VIIa-deficient mice. We showed that spectrin βV also associates with two USH1 proteins, sans (USH1G) and harmonin (USH1C). Spectrins are supposed to function as heteromers of α and β subunits, but fluorescence resonance energy transfer and in vitro binding experiments indicated that spectrin βV can also form homodimers, which likely supports its αII-independent βV functions. Finally, consistent with its distribution along the connecting cilia axonemes, spectrin βV binds to several subunits of the microtubule-based motor proteins, kinesin II and the dynein complex. We therefore suggest that spectrin βV homomers couple some USH1 proteins, opsin and other phototransduction proteins to both actin- and microtubule-based motors, thereby contributing to their transport towards the photoreceptor outer disks.

The remarkable hearing capacities of mammals arise from various evolutionary innovations. These include the cochlear outer hair cells and their singular feature, somatic electromotility, i.e., the ability of their cylindrical cell body to shorten and elongate upon cell depolarization and hyperpolarization, respectively. To shed light on the processes underlying the emergence of electromotility, we focused on the βV giant spectrin, a major component of the outer hair cells' cortical cytoskeleton. We identified strong signatures of adaptive evolution at multiple sites along the spectrin-βV amino acid sequence in the lineage leading to mammals, together with substantial differences in the subcellular location of this protein between the frog and the mouse inner ear hair cells. In frog hair cells, spectrin βV was invariably detected near the apical junctional complex and above the cuticular plate, a dense F-actin meshwork located underneath the apical plasma membrane. In the mouse, the protein had a broad punctate cytoplasmic distribution in the vestibular hair cells, whereas it was detected in the entire lateral wall of cochlear outer hair cells and had an intermediary distribution (both cytoplasmic and cortical, but restricted to the cell apical region) in cochlear inner hair cells. Our results support a scenario where the singular organization of the outer hair cells' cortical cytoskeleton may have emerged from molecular networks initially involved in membrane trafficking, which were present near the apical junctional complex in the hair cells of mammalian ancestors and would have subsequently expanded to the entire lateral wall in outer hair cells.unconventional spectrins | inner ear | F-actin cytoskeleton | cortical lattice | phylogenetics T he response of the mammalian auditory organ (cochlea) to acoustic stimuli in an extended frequency range (including high frequencies) has remarkable properties including very high sensitivity and exquisitely sharp tuning (1-3). These properties are the consequence of an evolutionary process that involved major morphological and functional changes. One of them is the emergence, in the cochlea, of the outer hair cells, a unique type of specialized sensory cells that display somatic electromotility, i.e., they undergo periodic length changes in response to the oscillation of their membrane potential evoked by the sound wave (they shorten upon depolarization and elongate upon hyperpolarization) (SI Appendix, Fig. S1 A-C). This process has endowed the mammalian auditory organ with a singular mechanism of spectral analysis of the acoustic stimulus through frequencyselective mechanical amplification (1-3), whereas spectral analysis in other vertebrates (fish, amphibians, reptiles, and birds) primarily relies on electrical tuning of the hair cells (4, 5).An intriguing question is how the emergence of somatic electromotility is related with the evolution of individual proteins involved in this process. The electromotility of outer hair cells critically depends on the presence, in th...

Abbreviations used in this paper: ABR, auditory brainstem response; DPO AE, distortion-product otoacoustic emission; E, embryonic day; IHC, inner hair cell; MET, mechanoelectrical transduction; MORN, membrane occupation and recognition nexus; OHC, outer hair cell; P, postnatal day; SPL, sound pressure level; USH, Usher syndrome.

Aggression is an ethologically important social behavior, but excessive aggression can be detrimental to fitness. Social experiences among conspecific individuals reduce aggression in many species, the mechanism of which is largely unknown. We found that loss-of-function mutation of nervy ( nvy ), a Drosophila homolog of vertebrate myeloid translocation genes (MTGs), increased aggressiveness only in socially experienced flies and that this could be reversed by neuronal expression of human MTGs. A subpopulation of octopaminergic/tyraminergic neurons labeled by nvy was specifically required for such social experience–dependent suppression of aggression, in both males and females. Cell type–specific transcriptomic analysis of these neurons revealed aggression-controlling genes that are likely downstream of nvy . Our results illustrate both genetic and neuronal mechanisms by which the nervous system suppresses aggression in a social experience–dependent manner, a poorly understood process that is considered important for maintaining the fitness of animals.

Aggression is an ethologically important social behavior1 but excessive aggression can be detrimental to animal fitness2,3. Social experiences among conspecific individuals reduce aggression in a wide range of animals4. However, the genetic and neural basis for the experience-dependent suppression of aggression remains largely unknown. Here we found that nervy (nvy), a Drosophila homolog of vertebrate myeloid translocation gene (MTG)5 involved in transcriptional regulation6–8, suppresses aggression via its action in a specific subset of neurons. Loss-of-function mutation of the nvy gene resulted in hyper-aggressiveness only in socially experienced flies, whereas overexpression of nvy suppressed spontaneous aggression in socially naïve flies. The loss-of-function nvy mutant exhibited persistent aggression under various contexts in which wild-type flies transition to escape or courtship behaviors. Knockdown of nvy in octopaminergic/tyraminergic (OA/TA) neurons increased aggression, phenocopying the nvy mutation. We found that a subpopulation of OA/TA cells specifically labeled by nvy is required for the social-experience-dependent suppression of aggression. Moreover, cell-type-specific transcriptomics on nvy-expressing OA/TA neurons revealed aggression-controlling genes that are likely downstream of nvy. Our results are the first to describe the presence of a specific neuronal subpopulation in the central brain that actively suppresses aggression in a social-experience-dependent manner, illuminating the underlying genetic mechanism.