The tension-sensitive actin-binding protein vinculin is preferentially recruited to the medial borders of HCs in a PTK7-dependent manner, providing evidence for anisotropic tension in the OC. molecular machinery underpinning hair bundle development and function. In this review, we spotlight recent advances in our understanding of hair bundle morphogenesis, with an emphasis on the molecular pathways governing hair bundle polarity and orientation. We next discuss the proteins and structural elements important for hair cell mechanotransduction as well as hair bundle cohesion and maintenance. In addition, developmental signals thought to regulate tonotopic features of hair cells are launched. Finally, novel methods that complement classic genetics for studying the molecular etiology of human deafness are offered. Introduction Humans have a highly developed sense of hearing that is critical for spoken communication. Hearing loss is usually a major public health issue affecting 48 million adults and 2C3 of every 1,000 children in the United States (Hearing Loss Association of America). A vast majority HJC0152 of congenital hearing loss is usually of sensorineural origin, due to defects in the sound processing machinery of the inner ear. Available treatments for hearing loss are currently very limited, and to develop new therapeutic interventions a fundamental understanding of the molecular physiology of hearing is critical. The prevalence of congenital hearing loss has both necessitated and facilitated genetic analysis of hearing in humans. Inherited forms of hearing loss can be syndromic, where hearing loss is usually associated with symptoms in other organs, or nonsyndromic, where hearing loss is the only deficit. Nonsyndromic hearing loss can be categorized based on inheritance patterns: DFNA for autosomal dominant, DFNB for autosomal recessive, DFN for X-linked forms and mitochondrial forms, which are only maternally inherited (observe Deafness and Hereditary Hearing Loss Overview http://www.ncbi.nlm.nih.gov/books/NBK1434/ for more details). Over 400 genetic syndromes that include hearing loss have been explained and nearly 100 genes responsible for inherited forms of deafness (deafness genes) recognized (observe Hereditary Hearing loss Homepage, http://hereditaryhearingloss.org/ for an updated deafness gene list). The identification of Rabbit Polyclonal to RED these genes has provided important entry points HJC0152 into understanding genetic regulation of hearing. To determine the function of human deafness genes, it is essential to use animal models. The mouse is usually a particularly attractive model because the anatomy and physiology of the auditory system is similar to that of humans, and tools for genetic manipulation are highly developed. Indeed, mouse knock-out mutations in orthologs of human deafness genes have provided important insights into the normal gene function and likely disease mechanisms. This is complemented by inner ear-specific conditional knock-out (cKO) of normally essential genes to further illuminate the genetic network and molecular pathways involved. Moreover, forward genetic screens in mice (and in zebrafish) have recognized new genes essential for hearing1C3. Together, these methods have begun to uncover the molecular underpinnings of auditory development and function. Here, we will review genes and pathways important for the development of sensory receptor cells in the hearing organ, with a specific focus on the morphogenesis of the stereociliary hair bundle, the mechanotransduction organelle that detects sound. For other critical aspects of sound transduction, readers are referred to a number of other excellent resources outlined in Further Reading/Resources. The machinery for sound transduction The auditory sensory epithelium The hearing organ HJC0152 of the inner ear is the spiral-shaped cochlea. It is composed of three fluid-filled chambers that lengthen along the length of the spiral. The two outer chambers, named the scala vestibuli and scala tympani, are filled with perilymph and sealed off from the centre chamber. The center chamber, the scala media or the cochlear duct, is usually filled with endolymph that baths the apical surface of the sensory epithelium, called the organ of Corti (OC) (Physique 1). The endolymph is usually rich in K+ and poor in Na+ and has a positive potential compared to perilymph. The basal surface of the OC is usually exposed to perilymph and sits around the basilar membrane, an elastic structure that vibrates in response to sound. The OC consists of one row of inner hair cells (IHC) and three rows of outer hair cells (OHC), interdigitated with non-sensory supporting cells (SC) (Physique 2A). Hair cells (HC) are sensory receptors for sound; IHCs transmit information to the brain, while OHCs amplify sound signals. In humans, there are approximately 3,500 IHCs and 12,000 OHCs, and HCs lost by genetic or environmental factors are not replaced by regenerative processes, leading to permanent hearing loss. Open in a separate window Physique 1 Cross-sectional diagram of the cochlear HJC0152 ductThe scala media, or cochlear duct, is usually shaded light blue and contains potassium-enriched endolymph secreted from your stria vascularis. The scala vestibuli and scala tympani, separated from your cochlear duct.