Stereocilia, or hair cells, line the inner ear and act as mechanosensors for hearing and vestibular function. Although hair cell loss was previously thought to be relatively permanent in mammals, scientists discovered that in vivo hair cell restoration is possible through overexpression of the genes Sox4 and Sox11. (Source: Wikimedia Commons, Bechara Kachar)
While hearing aids can help those with hearing impairments, there is currently no way to regenerate the sensory hair cells responsible for hearing and vestibular function in most mammals, including humans. However, a recent study suggests that genes involved in inner ear development may allow for future treatment and therapy for patients with hearing impairments.
Scientists at the Howard Hughes Medical Institute and Rockefeller University in New York discovered that the transcription factors Sox4 and Sox11 of the SoxC family play an important role in the development of the utricle and other sensory organs in the inner ear (1). Based on RNA sequencing and quantitative PCR data, scientists measured expression of these genes during embryogenesis and after birth (1). Although Sox4 and Sox11 were expressed in high levels in the utricle of mice during embryogenesis, gene expression decreased by 80% by two days after birth and 93% by the end of day seven (1).
To explore the functional role of Sox4 and Sox11 in inner ear development, researchers bred heterogeneous Sox4 and Sox11-deficient, conditional knockout mice (homogeneous mice were not viable) (1). The mutant mice exhibited small or irregular development of inner ear structures as well as vestibular dysfunction by four weeks of age (1). Additionally, when picked up by the tail in “tail-suspension tests,” the mice curled their trunks, let their heads bob, and circled, suggesting loss of balance and an inability to orient themselves. Mutant mice also had a 30-fold higher threshold for low frequency sounds at around four Hz than wild-type mice (1).
To determine the potential of Sox4 and Sox11 as therapies for hearing loss, scientists overexpressed these genes in the utricular maculae (the central region of the utricle) of adult mice using vectors (1). The overexpression of either Sox4 or Sox11 not only resulted in cell proliferation of SoxC expressing cells, but also generated new hair cells within four days (1). By day seven, cell cultures revealed a 13-fold and 10-fold increase in hair cell numbers in the Sox4 and Sox11 overexpressing utricular maculae, respectively (1).
The therapeutic implications of this study are that the treatment of hearing loss and even deafness, which would require complete generation and/or restoration of hair cells, is possible, and the key may be found in regulation or expression of SoxC transcription factors (1).
References
- Gnedeva K. & Hudspeth A.J. (26, October 2015) SoxC transcription factors are essential for the development of the inner ear. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1517371112