Representative expression patterns of genes controlling cochlear and vestibular specification. (A) Shh functions to maintain Pax2 and restrict Dlx5/Dlx6 in the medial wall of the otic vesicle in order to specify cochlear fate. Dlx5/Dlx6 specify the medial to dorsal most cells of the otic epithelium that give rise to the endolymphatic duct and vestibular apparatus. (B) Secretion of Shh from the notochord specifies the ventral most cells of the otic epithelium that express Otx1/Otx2 and possibly Pax2 which contribute to cochlear morphogenesis and outgrowth. In addition, Dlx5/Dlx6-dependent vestibular specifications and morphogenesis is dependent upon the activation of Gbx2 and Bmp4 function (not shown) and partial activation/expression of Otx1. Dlx5/Dlx6 also functions to restrict Pax2 expression to the medial wall of the otic vesicle epithelium. Thus, Dlx5/Dlx6 and Shh may functionally antagonize each other, through repression, to generate compartments of activities that specify the vestibular and cochlear cell fates. (C) Both Hmx2 and Hmx3 are required for cell fate determination and subsequent morphogenesis of the developing inner ear. Loss of both Hmx2 and Hmx3 results in the absence of the entire vestibular system. Msx1/Msx2 are expressed in the adjacent periotic mesenchyme and are critical for middle ear development. (D) Fgfs function with Shh in the periotic mesenchyme to initiate ventral otic capsule chondrogenesis via Brn4 and Tbx1 function (not shown). Fgfs are also expressed in the hindbrain epithelium adjacent to the otocyst and are important for induction of the otic placode.