Transient environmental exposures during mammalian development can permanently alter gene expression and metabolism by influencing the establishment of epigenetic gene regulatory mechanisms. The genomic characteristics that confer such epigenetic plasticity upon specific loci, however, have not been characterized. Methyl donor supplementation of female mice before and during pregnancy permanently increases DNA methylation at the viable yellow agouti (A(vy)) metastable epiallele in the offspring. The current study tested whether another murine metastable epiallele, axin fused (Axin(Fu)), similarly exhibits epigenetic plasticity to maternal diet. We found that methyl donor supplementation of female mice before and during pregnancy increased DNA methylation at Axin(Fu) and thereby reduced by half the incidence of tail kinking in Axin(Fu)/+ offspring. The hypermethylation was tail-specific, suggesting a mid-gestation effect. Our results indicate that stochastic establishment of epigenotype at metastable epialleles is, in general, labile to methyl donor nutrition, and such influences are not limited to early embryonic development.
The microenvironment of the cochlea is maintained by the barrier between the systemic circulation and the fluids inside the stria vascularis. However, the mechanisms that control the permeability of the intrastrial fluid-blood barrier remain largely unknown. The barrier comprises endothelial cells connected to each other by tight junctions and an underlying basement membrane. In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of perivascular cells with both macrophage and melanocyte characteristics. The perivascular-resident macrophage-like melanocytes (PVM/Ms) are in close contact with vessels through cytoplasmic processes. Here we demonstrate that PVM/Ms have an important role in maintaining the integrity of the intrastrial fluid-blood barrier and hearing function. Using a cell culture-based in vitro model and a genetically induced PVM/M-depleted animal model, we show that absence of PVM/Ms increases the permeability of the intrastrial fluid-blood barrier to both lowand high-molecular-weight tracers. The increased permeability is caused by decreased expression of pigment epithelial-derived factor, which regulates expression of several tight junction-associated proteins instrumental to barrier integrity. When tested for endocochlear potential and auditory brainstem response, PVM/ M-depleted animals show substantial drop in endocochlear potential with accompanying hearing loss. Our results demonstrate a critical role for PVM/Ms in regulating the permeability of the intrastrial fluid-blood barrier for establishing a normal endocochlear potential hearing threshold. mouse cochlea | paracellular permeability | tight junction | capillary T he intrastrial fluid-blood barrier separates the stria vascularis (SV) from peripheral circulation. The integrity of the barrier is critical for maintaining inner ear homeostasis, especially for sustaining the endocochlear potential (EP), an essential driving force for hearing function (1-4). Disruption of the barrier is closely associated with a number of hearing disorders, including autoimmune inner ear disease, noise-induced hearing loss, agerelated hearing loss, and several genetically linked diseases (5-10). Despite the importance of the intrastrial fluid-blood barrier, little is understood about regulation of the barrier and the mechanisms that control its permeability.In the classic view, the intrastrial fluid-blood barrier comprises basement membrane and endothelial cells (ECs) that connect to each other with tight junctions (11) to form a diffusion barrier that prevents most blood-borne substances from entering the ear (2). In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of pericytes and perivascular-resident macrophage-like melanocytes (PVM/Ms) (12, 13). The PVM/Ms are not observed in other capillary regions such as in capillary beds of the spiral ligament. The PVM/Ms are in close contact with vessels through cytoplasmic processes. The structural complexity of PVM/Ms' capillar...
The ear is a remarkably sensitive pressure fluctuation detector. In guinea pigs, behavioral measurements indicate a minimum detectable sound pressure of ~20 μPa at 16 kHz. Such faint sounds produce 0.1 nm basilar membrane displacements, a distance smaller than conformational transitions in ion channels. It seems that noise within the auditory system would swamp such tiny motions, making weak sounds imperceptible. Here, a new mechanism contributing to a resolution of this problem is proposed and validated through direct measurement. We hypothesize that vibration at the apical end of hair cells is enhanced compared to the commonly measured basilar membrane side. Using in vivo optical coherence tomography, we demonstrated that apical-side vibrations peak at a higher frequency, had different timing, and were enhanced compared to the basilar membrane. These effects depend nonlinearly on the stimulus level. The timing difference and enhancement are important for explaining how the noise problem is circumvented.
Permanent hearing loss affects more than 5% of the world’s population, yet there are no nondevice therapies that can protect or restore hearing. Delivery of therapeutics to the cochlea and vestibular system of the inner ear is complicated by their inaccessible location. Drug delivery to the inner ear via the vasculature is an attractive noninvasive strategy, yet the blood-labyrinth barrier at the luminal surface of inner ear capillaries restricts entry of most blood-borne compounds into inner ear tissues. Here, we compare the blood-labyrinth barrier to the blood-brain barrier, discuss invasive intratympanic and intracochlear drug delivery methods, and evaluate noninvasive strategies for drug delivery to the inner ear.
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