The Role of Connexin and Pannexin Large-Pore Channels in Hearing

Connexin and pannexin large-pore channels allow the regulated passage of small molecules at sites of cell-cell contacts, and from the cytosol to the extracellular milieu, respectively. Since it has been known for many years that Cx26 and Cx30 gap junction proteins are crucial in hearing we propose that Cx43 might also be important in hearing. Here we used two different genetically modified mouse lines that contain systemic Cx43 gene mutations that reduces gap junctional intercellular communication (GJIC) to examine whether Cx43 is also important for proper hearing function. Furthermore, since pannexins have also been postulated to be involved in auditory function we used three different Panx global knock-out mice to evaluate their hearing profiles. We showed that Cx43 mutant mice that had severe loss of Cx43 channel function had hearing loss, while mutant mice with a modest loss of Cx43 function exhibited normal hearing. Surprisingly, Panx1-/-, Panx3-/-, and double knock-out (dKO) mice did not have hearing loss, suggesting that pannexins do not play an important role in hearing. To evaluate whether large-pore channels played a role in noise-induced hearing loss (NIHL), we challenged Cx43 mutant and pannexin knock-out mice with a loud noise-exposure and examined their permanent hearing loss. Interestingly, only Panx3-/- and Panx dKO mice were slightly protected against permanent hearing damage. Finally, organotypic cochlear cultures from Cx43 mutant mice and a CRISPR Cas9 Cx43 ablated cochlear-derived cell line, revealed that GJIC does not exacerbate drug-induced hearing loss but does cause supporting cell reorganization. Collectively, our results highlight the importance of Cx43 GJIC in hearing function, but not noise- or drug-induced ototoxicity. Furthermore, our studies support the notion that Panxs are not involved in baseline hearing, but loss of Panx3 may lead to slight protection against permanent NIHL

The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by GJB2) and Cx30 (GJB6) are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss. Here, we report that the Cx30-A88V mutant, despite being toxic to inner ear-derived HEI-OC1 cells, conferred remarkable long-term protection against age-related high frequency hearing loss in Cx30(A88V/A88V) mice. During early development, there were no overt structural differences in the cochlea between genotypes, including a normal complement of hair cells; however, the supporting cell Cx30 gap junction plaques in mutant mice were reduced in size. In adulthood, Cx30(A88V/A88V) mutant mice had a reduction of cochlear Cx30 mRNA and protein, yet a full complement of hair cells. Conversely, the age-related high frequency hearing loss in Cx30(+/+) and Cx30(+/A88V) mice was due to extensive loss of outer hair cells. Our data suggest that the Cx30-A88V mutant confers long-term hearing protection and prevention of hair cell death, possibly via a feedback mechanism that leads to the reduction of total Cx30 gap junction expression in the cochlea

Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss

Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43(I130T/+) mutant mice, with similar to 50% Cx43 channel function, did not have any hearing loss, Cx43(G60S/+) mutant mice, with similar to 20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43(I130T/+) mice with a loud noise and found that they had a similar susceptibility to noise-induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing. This article has an associated First Person interview with the first author of the paper

Expression of 8-oxoguanine DNA glycosylase (Ogg1) in mouse retina

International audienc

CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation

CX3CR1 expression is associated with the commitment of CSF-1R+ myeloid precursors to the macrophage/dendritic cell (DC) lineage. However, the relationship of the CSF-1R+ CX3CR1+ macrophage/DC precursor (MDP) with other DC precursors and the role of CX3CR1 in macrophage and DC development remain unclear. We show that MDPs give rise to conventional DCs (cDCs), plasmacytoid DCs (PDCs), and monocytes, including Gr1+ inflammatory monocytes that differentiate into TipDCs during infection. CX3CR1 deficiency selectively impairs the recruitment of blood Gr1+ monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs

Estrogen and Progestogen Correlates of the Structure of Female Copulation Calls in Semi-Free-Ranging Barbary Macaques (Macaca sylvanus)

Females of many Old World primates produce conspicuous vocalizations in combination with copulations. Indirect evidence exists that in Barbary macaques (Macaca sylvanus), the structure of these copulation calls is related to changes in reproductive hormone levels. However, the structure of these calls does not vary significantly around the timing of ovulation when estrogen and progestogen levels show marked changes. We here aimed to clarify this paradox by investigating how the steroid hormones estrogen and progesterone are related to changes in the acoustic structure of copulation calls. We collected data on semi-free-ranging Barbary macaques in Gibraltar and at La Forêt des Singes in Rocamadour, France. We determined estrogen and progestogen concentrations from fecal samples and combined them with a fine-grained structural analysis of female copulation calls (N = 775 calls of 11 females). Our analysis indicates a time lag of 3 d between changes in fecal hormone levels, adjusted for the excretion lag time, and in the acoustic structure of copulation calls. Specifically, we found that estrogen increased the duration and frequency of the calls, whereas progestogen had an antagonistic effect. Importantly, however, variation in acoustic variables did not track short-term changes such as the peak in estrogen occurring around the timing of ovulation. Taken together, our results help to explain why female Barbary macaque copulation calls are related to changes in hormone levels but fail to indicate the fertile phase

Werewolf, there wolf : Variants in hairless associated with hypotrichia and roaning in the lykoi cat breed

Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non‐lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.Peer reviewe

ATM et OGG1 (ataxia telangiectasia mutated et 8-oxoguanine ADN glycosylase) (Etude de deux enzymes majeures impliquées dans la reconnaissance des lésions de l'ADN dans l'oeil de souris)

La rétine est un tissu fortement exposé au stress oxydatif de part son activité physiologique (exposition aux rayons lumineux, consommation d'oxygène, activité métabolique, phagocytose...). Toutes ces particularités sont à l'origine de la production de ROS qui provoquent des nombreux dommages comme l'oxydation des bases et les cassures double brin. Ce travail présente différentes protéines de la réparation de l'ADN (ATM et OGG1) intervenant dans différentes voies de reconnaissance suivant le type de dommages rencontrés. La protéine ATM qui détecte des cassures double brin présente une localisation différente dans les photorécepteurs et les cellules granulaires du cervelet. La protéine OGG1 permettant la reconnaissance et l'excision de la 8-oxoG est présente et active dans les cellules rétiniennes. Chez les souris déficientes pour chacune de ces protéines, aucune dégénérescence rétinienne n'est observée. Cependant, des dysplasies de la neurorétine et de l'EPR sont mises en évidence.The retina is particularly susceptible to oxidative stress due to high oxygen consumption and metabolic rates. The specific characteristics of the retina (high levels of oxygen consumption, light, polyunsatured fatty acids...) lead to free radical, cell damages, ageing and diseases. Therefore, all these processes can contribute to the formation of oxidative DNA damage in the retinal cells. A difference between the localization patterns of the active and inactive forms of ATM in photoreceptor and granular cells was observed. This suggests that ATMp (activated form) may be involved in both the protection of cells from oxidative damage and the maintenance of ocular cell structure and function. OGG1, responsible for the recognition and excision of the 8-oxoG, is highly expressed in neuroretina and non-neuronal cells of the eye and a 8-oxoG DNA-glycosylase activity is detected in this tissue. Moreover, there is no retinal degeneration in Atm-/- and Ogg1-/- mice.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF