Hair cell fate decisions in cochlear development and regeneration

Abstract

The discovery of avian cochlear hair cell regeneration in the late 1980's and the concurrent development of new techniques in molecular and developmental biology generated a renewed interest in understanding the genetic mechanisms that regulate hair cell development in the embryonic avian and mammalian cochlea and regeneration in the mature avian cochlea. Research from many labs has demonstrated that the development of the inner ear utilizes a complex series of genetic signals and pathways to generate the endorgans, specify cell identities, and establish innervation patterns found in the inner ear. Recent studies have shown that the Notch signaling pathway, the Atoh1/Hes signaling cascade, the stem cell marker Sox2, and some of the unconventional myosin motor proteins are utilized to regulate distinct steps in inner ear development. While many of the individual genes involved in these pathways have been identified from studies of mutant and knockout mouse cochleae, the interplay of all these signals into a single systemic program that directs this process needs to be explored. We need to know not only what genes are involved, but understand how their gene products interact with one another in a structural and temporal framework to guide hair cell and supporting cell differentiation and maturation. KeywordsCochlea; Hair Cell; Supporting Cell; Genetic Regulation; Notch Pathway; Development; Regeneration Hearing impairment affects almost 49 million people in the US and over 249 million worldwide. Approximately 17% of children under age 18 have a hearing loss and the incidence increases with age: roughly 30% of people over 65 and over 90% of people over 80 have a substantial hearing loss. Although rarely life-threatening, hearing loss affects more people than epilepsy, multiple sclerosis, spinal injury, stroke, Huntington's and Parkinson's diseases combined (Hudspeth, 1997) and has a huge financial impact on our economy and lifestyle. Hearing impairment is mainly caused by damage to the hair cells, the sensory cells in the cochlea (Figure 1). In mammals, the absence of these cells results in permanent hearing loss

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

“…The Wnt/ β-catenin, Notch, Jak/Stat, Bmp, and Fgf pathways are important for hair cell development as well as for the regeneration of hair cells in fish and chick epithelia (15,23,43). Our understanding of which pathways act upstream and how these pathways affect each other is still very limited.…”

“…Our analyses focused on pathways involved in hair cell development as they might be reused during regeneration (15,23,43,78,79). For example, Wnt/β-catenin signaling is crucial for the development of many organs across the animal kingdom (80).…”

“…Work in birds has shed light on the mechanisms regulating sensory hair cell regeneration in vertebrates (2,4,(11)(12)(13)(14)(15)(16)(17)(18). For instance, during sensory hair cell regeneration in the chick, the majority of hair cells arise by proliferation of neighboring support cells (19).…”

miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

“…Cochlear hair cells are specified during embryonic development (34), and from about embryonic day 14-16, IHCs and OHCs in the mouse are recognizable by their different hair bundle morphology and location within the sensory epithelium (24,33). However, throughout embryonic development, their biophysical characteristics are qualitatively indistinguishable (10).…”

Thérapie cellulaire dans l’oreille interne

“…Plusieurs innovations morpho-fonctionnelles (apparition de l'oreille moyenne et externe, allongement de l'organe sensoriel auditif, apparition de la membrane basilaire sur laquelle repose l'épithélium auditif, émergence de deux types de cellules sensorielles distinctes : les cellules sensorielles courtes et longues chez les oiseaux, CCI et CCE chez les mammifères) ont accompagné l'amélioration des performances du système auditif, tant en ce qui concerne la localisation de la source sonore que la sensibilité et la gamme fréquentielle des sons perçus [2,3]. Pour des raisons encore mal comprises, la capacité de régénération des cellules ciliées tout au long de la vie de l'animal a été perdue chez les mammifères [4][5][6][7]. Ainsi chez l'homme, le nombre de cellules ciliées est fixé avant la naissance, et leur atteinte, dans la cochlée comme dans le vestibule, entraîne un déficit sensoriel irréversible.…”