Hair Cell Regeneration In Birds Research Articles

Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium

Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors.

Gene Expression Analysis of Forskolin Treated Basilar Papillae Identifies MicroRNA181a as a Mediator of Proliferation

BackgroundAuditory hair cells spontaneously regenerate following injury in birds but not mammals. A better understanding of the molecular events underlying hair cell regeneration in birds may allow for identification and eventually manipulation of relevant pathways in mammals to stimulate regeneration and restore hearing in deaf patients.Methodology/Principal FindingsGene expression was profiled in forskolin treated (i.e., proliferating) and quiescent control auditory epithelia of post-hatch chicks using an Affymetrix whole-genome chicken array after 24 (n = 6), 48 (n = 6), and 72 (n = 12) hours in culture. In the forskolin-treated epithelia there was significant (p<0.05; >two-fold change) upregulation of many genes thought to be relevant to cell cycle control and inner ear development. Gene set enrichment analysis was performed on the data and identified myriad microRNAs that are likely to be upregulated in the regenerating tissue, including microRNA181a (miR181a), which is known to mediate proliferation in other systems. Functional experiments showed that miR181a overexpression is sufficient to stimulate proliferation within the basilar papilla, as assayed by BrdU incorporation. Further, some of the newly produced cells express the early hair cell marker myosin VI, suggesting that miR181a transfection can result in the production of new hair cells.Conclusions/SignificanceThese studies have identified a single microRNA, miR181a, that can cause proliferation in the chicken auditory epithelium with production of new hair cells.

Hair Cell Regeneration

Hair Cell Regeneration

末梢前庭器から前庭神経核へ―最近の知見―９． 末梢前庭器における再生

Hair cell regeneration has been gradually shown to occur in the inner ears of mammals as well as birds; this has been particularly demonstrated in the vestibular system rather than the organ of Corti. Several new strategies including mitosis, self repair, transdifferentiation, and cell transplantation are being pursued to brimg about hair cell regeneration. This review discusses the field of inner ear hair cell regeneration in birds and mammals, and the relationship of inner ear regeneration to functional recovery.

Functional recovery of anterior semicircular canal afferents following hair cell regeneration in birds.

Streptomycin sulfate (1.2 g/kg i.m.) was administered for 5 consecutive days to 5-7-day-old white Leghorn chicks; this causes damage to semicircular canal hair cells that ultimately regenerate to reform the sensory epithelium. During the recovery period, electrophysiological recordings were taken sequentially from anterior semicircular canal primary afferents using an indentation stimulus of the canal that has been shown to mimic rotational stimulation. Chicks were assigned to an early (14-18 days; n = 8), intermediate (28-34 days; n = 5), and late (38-58 days; n = 4) period based on days after treatment. Seven untreated chicks, 15-67 days old, provided control data. An absence of background and indent-induced discharge was the prominent feature of afferents in the early period: only "silent" afferents were encountered in 5/8 experiments. In several of these chicks, fascicles of afferent fibers were seen extending up to the epithelium that was void of hair cells, and intra- and extracellular biocytin labeling revealed afferent processes penetrating into the supporting cell layer of the crista. In 3/8 chicks 74 afferents could be characterized, and they significantly differed from controls (n = 130) by having a lower discharge rate and a negligible response to canal stimulation. In the intermediate period there was considerable variability in discharge properties of 121 afferents, but as a whole the number of "silent" fibers in the canal nerve diminished, the background rate increased, and a response to canal stimulation detected. Individually biocytin-labeled afferents had normal-appearing terminal specializations in the sensory epithelium by 28 days poststreptomycin. In the late period, afferents (n = 58) remained significantly different from controls in background discharge properties and response gain. The evidence suggests that a considerable amount of variability exists between chicks in the return of vestibular afferent function following ototoxic injury and that the secretory function of regenerating hair cells might become functional before their transducer function.

New studies on hair cell regeneration in birds

The discovery of hair cell regeneration in birds a little over a decade ago raises a number of obvious and exciting questions about basic functional and neural plasticity in the vertebrate auditory system. Because many birds must learn the complex, species-specific, acoustic signals they use for communication just as humans must learn the sounds of speech, the finding of hair cell regeneration in birds also raises other interesting questions. One of these questions concerns the relation between hearing loss and vocal production. Another question concerns the effect of full or partial hearing recovery on vocal behavior. The purpose of this paper is to review what is known about the functional (i.e. behavioral) consequences of hair cell loss and subsequent hair cell regeneration in birds, to point out the relevance of this work for human hearing recovery, and to suggest some directions for future research.

Cellular studies of auditory hair cell regeneration in birds.

A decade ago it was discovered that mature birds are able to regenerate hair cells, the receptors for auditory perception. This surprising finding generated hope in the field of auditory neuroscience that new hair cells someday may be coaxed to form in another class of warm-blooded vertebrates, mammals. We have made considerable progress toward understanding some cellular and molecular events that lead to hair cell regeneration in birds. This review discusses our current understanding of avian hair cell regeneration, with some comparisons to other vertebrate classes and other regenerative systems.

The resolution of frequency and time following hair cell regeneration in birds

Detection thresholds, auditory filter widths, and temporal modulation transfer functions were measured in European starlings before, during, and after a 10-day injection series of kanamycin, an ototoxic aminoglycoside antibiotic. Hearing loss in response to the drug exposure was observed in frequencies at or above 3 kHz; threshold shifts above 3 kHz were ≳60 dB. The auditory filter broadened at 5 kHz from 9% to 20% of center frequency (CF). After 60 days of recovery, detection thresholds improved to within 15 dB of predose estimates, and auditory filters at 5 kHz recovered to 11% of CF and were permanently changed in the skew toward lower frequencies. At 3 and 1 kHz, changes in filter bandwidths were small and transient. At 3 kHz, no permanent change in filter width occurred, but filters were permanently skewed toward lower frequencies. At 1 kHz, changes in skew occurred, but only during the period of greatest threshold shift at higher frequencies. Temporal resolution was largely unaffected by hearing loss, although some loss in sensitivity to amplitude modulation was observed during the period of profound hearing loss. The data are discussed in terms of the relation among auditory functions and the perception of birdsong by starlings after hair cell regeneration.

Hair cell regeneration

In 1988, two landmark papers definitively showed that hair cells in the mature avian inner ear can regenerate after otologic insults have destroyed the existing receptors. This discovery, not new to the vertebrate phylum but new for terrestrial vertebrates, has led to a rethinking of the assumption that hair cell loss in mammals, including humans, must necessarily be permanent. In this article, we present a brief progress report on the status of research on hair cell regeneration in birds and mammals. In the brief period since these initial publications, a great deal has been accomplished; we now know much about the process of hair regeneration in birds. We know that it does lead to a recovery of function(s), and we are beginning to get clues about the cellular and molecular events that trigger hair cell regeneration in birds. In mammals, intriguing data are emerging that suggest induction of early stages of the regeneration process, as well as the possibility that more than one cellular route for hair cell replacement may exist. These data do not provide a cure for hearing loss or dizziness, but they do provide a new beacon shining light down a long tunnel, the entrance to which has only recently been opened.