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First published online August 18, 2004
doi: 10.1242/10.1242/dev.01339

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From placode to polarization: new tunes in inner ear development

¹ Department of Cell and Developmental Biology, Program in Neuroscience, Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109-0616, USA
² Section on Developmental Neuroscience, National Institute on Deafness and other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA

View larger version (27K): [in a new window]   Fig. 1. Development of the otocyst. (A) Cross-section through a developing embryo at the level of the hindbrain (dorsal towards the top). The otic placode forms as a thickening of the surface ectoderm (blue) adjacent to the hindbrain (HB) and notochord (NC). The space between the hindbrain and the surface ectoderm is populated by periotic mesenchymal cells and some neural crest cells (pink). (B) As development continues, the placodes pinch off to form otic vesicles (purple). (C) Soon after closure of the otocyst (purple), neuroblasts (yellow), which give rise to the statoacoustic ganglion, delaminate from the anteroventral surface of the otocyst. (D) Next, the otocyst undergoes elaborate morphogenetic changes, including the dorsal extension of the endolymphatic ducts (ED), which will terminate in the endolymphatic sacs (not shown), in the dorsal region of the developing otocyst and the cochlear duct (CD) in the ventral region. (E) As development continues, the cochlear duct begins to coil and the semicircular canals (SSC) begin to form in the dorsal region of the ear. Developing sensory patches are illustrated in green. At the same time, periotic mesenchymal cells (pink) condense around the developing ear to form the bony labyrinth.

View larger version (75K): [in a new window]   Fig. 2. Anatomy of the adult mammalian cochlea. (A) Cross-section through the human head, illustrating the position of the inner ear. The ear has three parts: the external ear, which consists of the pinna and external auditory meatus (EAM) and ends at the tympanic membrane (TM, green); the middle ear (ME, orange), which contains the three middle ear bones; and the inner ear, which includes the bony labyrinth (BL, light blue) and the statoacoustic ganglion (SAG, purple). (B) Lateral view of the mouse inner ear (boxed region in A) with sensory epithelia in green. LC, lateral semicircular canal; SC, superior semicircular canal; PC, posterior semicircular canal; Sac, saccule; Utr, utricle; Coch, cochlea; ES, endolymphatic sac. The endolymphatic duct is hidden from view but connects the ES to the semicircular canals. (C) Cross-section through the boxed region in B, illustrating the anatomy of the cochlear duct. The duct is separated into scala vestibule (SV), scala media (SM) and scala tympani (ST). The sensory epithelium of the cochlea, the organ of Corti (boxed), is located on the floor of the scala media. (D) Cross-section of the organ of Corti, containing a single inner hair cell (I, green), three outer hair cells (1-3, green) and non-sensory supporting cells (blue), which include the pillar cells (purple). Inner and outer sensory hair cells are separated by the tunnel of Corti (TC), a fluid filled structure that is bounded by inner and outer pillar cells (IP and OP, purple).

View larger version (20K): [in a new window]   Fig. 3. Inductive interactions that regulate otocyst induction and ventral patterning. (A) Cross-section of a developing vertebrate embryo at the level of rhombomeres 4 and 5. Prior to placodal induction, a group of transcription factors, including Dlx3b, Dlx4b, Sox9a and Foxi1 are expressed in the preplacodal ectoderm (blue). Simultaneously, the hindbrain (HB) secretes Fgf3 (green), which acts as an inducer for the otic placode. (B) At the same time, periotic mesenchyme (POM) located between the hindbrain and placodal ectoderm produces either Fgf10- or Fgf19/15- (red) inducing agents, depending on the species. (C) The combined expression of Fgf3 (green) and either Fgf10 or Fgf19/15 (red) generates a combinatorial code (yellow) that induces placodal development in a specific region of the ectoderm (purple). (D) After closure of the otocyst, ventral phenotypes are induced through a combination of the expression of the transcription factor Six1 (orange) in the ventral region of the otocyst and long-range signaling by Shh (pink). Shh originates in the notochord and floorplate to influence the formation of both otocysts (although the presumed signaling interactions are only illustrated for the left side).

View larger version (11K): [in a new window]   Fig. 4. Development of the cochlear duct and organ of Corti. Each drawing illustrates a cross-section through the developing mammalian cochlear duct. (A) At E12.5, the duct consists of undifferentiated epithelial cells. A subset of cells located within the duct expresses Fgfr1 (pink). Expression of Fgfr1 appears to correlate with the region of the duct will develop into the greater epithelial ridge (GER, green outline) and organ of Corti (OC, red outline). (B) By E16.5, individual hair cells (yellow) begin to differentiate within the OC. Fgfr1 expression continues in the GER and OC (red outline). In addition, a subset of cells within the OC begins to express Fgfr3 (blue) and Fgfr1 (overlap of Fgfr1 and Fgfr3 expression appears as purple). (C) By E18.5, the basic cellular pattern of the OC is complete. A single inner hair cell (IC, yellow) and three outer hair cells (1-3, yellow) are present at this stage. In addition, inner and outer hair cells are separated by the developing pillar cells (labeled as OP and IP) that will give rise to the tunnel of Corti. By this time, expression of Fgfr1 (pink) has become restricted to the outer hair cells and Deiter's cells (another type of non-sensory supporting hair cell), while Fgfr3 expression (blue) is restricted to the pillar cells.

View larger version (21K): [in a new window]   Fig. 5. Effects of modulating gene expression on development of the organ of Corti (OC). (A) Ectopic expression of Math1 (Atoh1) in individual cells within the greater epithelial ridge (GER) (green outline) results in the formation of hair cells (filled in green) in the GER. (B) Hypomorphic Fgfr1 produces small sensory islands that consist of inner hair cells (IC, yellow), an increased number of pillar cells (pink) and no outer hair cells. (C) Deletion of Fgfr1 leads to a nearly complete disruption in the formation of the OC (red outline) with no identifiable cell types. (D) Deletion of Fgfr3 or inhibition of FGFR3 activity results in a disruption in the differentiation of pillar cells (outlined in pink). Compare the shape of the pillar cells in this drawing with the normal shape of the pillar cells illustrated in Fig. 4. (E) Increased activation of Fgfr3 leads to an overproduction of pillar cells but no significant affects on formation of either inner hair cells (IC) or outer hair cells (1-3, yellow).

View larger version (40K): [in a new window]   Fig. 6. Generation of stereociliary bundle orientation. (A,B) Side and lumenal views of a hair cell illustrating the morphology of the mechanosensitive stereociliary bundle. The stereocilia (green) are arranged in a staircase pattern with a single microtubule-based kinocilium (red) located at one edge. (C) Each circle illustrates the lumenal surface of a developing hair cell at different time points. (C1) Prior to bundle formation, all developing hair cells have a single cilium (red) that will develop as the kinocilium. (C2) As development proceeds, the cilium moves from the center of the lumenal surface towards the periphery (arrow). Most cilia move to a position that approximates their final orientation. (C3) Next, the developing stereociliary bundle (kinocilium in red and stereocilia in green) moves along the peripheral edge of the cell (arrows) to attain its final orientation. (C4) Progressive refinements ultimately result in the development of appropriate orientation. (D) Hypothetical expression patterns for molecules that regulate bundle orientation. (D1) Vangl2 (blue), Celsr1 (yellow) and Scrb1 (purple) are thought to be expressed initially throughout hair cells. (D2) Prior to the centrifugal movement of the cilium, Vangl2 is localized to the side of the developing cell opposite the site of stereociliary bundle formation (the proximal side) and Celsr1 is localized to both the proximal and distal sides of the cell. (D3,D4) Wnt (dark shading) is thought to be distributed in a gradient around the developing hair cell. Following centrifugal movement, outer hair cells reorient their bundles towards the point of lowest Wnt concentration. (E) Effects of different mutations on bundle orientation. Mutations in Vangl2 (E2) result in a defect in the direction of centrifugal movement. Similar effects are assumed for Scrb1 (E3) or Celsr1 (E4) mutants. (F) Disruption of the Wnt gradient, either an excess of Wnt (F2) or a deficiency (F3), results in inhibition of the bundle reorientation.