REVIEWS The selective advantage of sensitive hearing to monitor the environment and communicate has produced vari- ous morphologies of hearing organs in vertebrate species 1,2 . Although the physiological mechanisms that underlie the sensitivity and frequency selectivity of hearing might differ between mammalian and non- mammalian species 2,3 , there is a recurrent architectural theme in hearing organs: they all use hair cells to detect mechanical stimuli and convert them into afferent nerve signals that are directed towards the brain 4 . The mammalian inner ear contains approximately 15,000–30,000 neurosensory hair cells. These cells are located inside the temporal bone of the cranium, which makes their post-mortem isolation a daunting task in many mammalian species, including humans. For this reason, much of what is known about the structure and function of hair cells has been derived from studies of non-mammalian species, including frogs, turtles and chickens. However, many of the proteins that are involved in the morphogenesis of hair cells have been identified through the positional cloning of genes that are responsible for different forms of hereditary deafness in humans, or through the analysis of mouse models of hereditary hearing loss 5 . Surprisingly, many intracellular motor and intercellular adhesion molecules have been implicated in hair cell morphogenesis. Only recently has it become possible to incorporate the insights from all of these studies into integrated, testable models of hair cell morphogenesis. Here, we review these models and the genes involved in the ‘micro-morphogenesis’ of struc- tural elements that are required for the mechanosensi- tivity of hair cells. These morphogenetic events include changes in actin packing and the contour of the hair cell’s mechanosensory organelle (the STEREOCILIUM), adhesion of adjacent stereocilia to form a hair bundle and elongation of stereocilia to form a staircase-shaped bundle. Irreversible hair cell degeneration is a common feature of many genetic and environmental forms of hearing loss, and our evolving knowledge of hair cell morphogenesis could eventually lead to strategies to prevent, reduce or reverse hearing loss caused by hair cell damage. Development of the inner ear in mammals The mammalian inner ear consists of the cochlea, a snail-shaped organ that mediates sound transduc- tion, and the vestibular labyrinth, which detects grav- itational force, and angular and linear accelerations (FIG. 1a,b). The extraordinary ability of the mammalian cochlea to detect and distinguish sounds over a wide range of frequencies depends on the precise organiza- tion of its highly specialized neurosensory epithelium, GENETIC INSIGHTS INTO THE MORPHOGENESIS OF INNER EAR HAIR CELLS Gregory I. Frolenkov*, Inna A. Belyantseva ‡ , Thomas B. Friedman ‡ and Andrew J. Griffith* § The mammalian inner ear is a sensory organ that has specialized hair cells that detect sound, as well as orientation and movement of the head. The ‘hair’ bundle on the apical surface of these cells is a mechanosensitive organelle that consists of precisely organized actin-filled projections known as stereocilia. Alterations in hair-bundle morphogenesis can result in hearing loss, balance defects or both. Positional cloning of genes that underlie hereditary hearing loss, coupled with the characterization of corresponding mouse models, is revealing how hair cells have adapted the molecular mechanisms of intracellular motility and intercellular adhesion for the morphogenesis of their apical surfaces. STEREOCILIUM (Pl. stereocilia). A large, rigid, actin-filled microvillus on the apical surface of hair cells in the inner ear. NATURE REVIEWS | GENETICS VOLUME 5 | JULY 2004 | 489 *Section on Gene Structure and Function; ‡ Section on Human Genetics, Laboratory of Molecular Genetics; § Hearing Section, Neuro-Otology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA. Correspondence to A.J.G. e-mail: griffita@nidcd.nih.gov doi:10.1038/nrg1377 FOCUS ON ORGANOGENESIS