The homeobox gene Emx2 underlies middle ear and inner ear defects in the deaf mouse mutant pardon

Abstract

The semi-dominantly inherited mouse mutation pardon (Pdo) was isolated due to the lack of a Preyer reflex (ear flick) in response to sound from a large-scale N -ethyl- N -nitrosourea (ENU) mutagenesis programme. Dissection of the middle ear revealed malformations in all three ossicles, rendering the ossicular chain incomplete. Hair cell counts in the apical turn of the organ of Corti revealed a significant 22.7% increase in the number of outer hair cells. Raised compound action potential thresholds in Pdo/+ mutants suggested a combined sensorineural/conductive hearing loss. We show that a missense mutation in the homeobox gene Emx2 is responsible for these defects, identifying a new function for this gene in the development of specific structures in the ear.

Joint formation in the middle ear: Lessons from the mouse and guinea pig

“…Emx2, therefore, appears to identify not only the incus but the joint region as well. This fits in with the fact that in the Emx2 knockout, in addition to loss of the incus, the malleus lacks its articulating surface (Rhodes et al, 2003). In a similar fashion to the articulation of the incus with the malleus, the illium of the hind limb normally articulates with the sacral vertebrae.…”

“…In the mouse, Emx2 has been shown to play a role specifically in the formation of the incus, as the incus is lost in the Emx2 knockout (Rhodes et al, 2003). The expression pattern of Emx2 in the middle ear, however, has not been shown.…”

“…Emx2 mutant heterozygotes have a defect in the joint articulation between the malleus and the incus with the incus being much smaller creating a circular rather than a double V-shape. The homozygote completely lacks an incus and the articulation for the missing incus on the malleus is defective (Rhodes et al, 2003).…”

Characterization of a novel ENU-generated myosin VI mutant mouse strain with congenital deafness and vestibular dysfunction

“…This strain, charlie, was generated in an Nethyl-N-nitrosourea (ENU)-mutagenesis and breeding program at the Australian Phenomics Facility (APF, Canberra, Australia). ENUmutagenesis programs have proven to be a highly valuable approach in identifying novel mutations and genes involved in the auditory pathway, as well as revealing novel functions of genes already known to be involved in hearing (Curtin et al, 2003;Hardisty et al, 2003;Hrabe de Angelis et al, 2000;Kiernan et al, 2001;Marcotti et al, 2006;Nolan et al, 2000;Rhodes et al, 2004Rhodes et al, , 2003Tsai et al, 2001;Vreugde et al, 2002). Initially, ENUmutagenesis programs focused on dominant disease-causing mutations, however, as the majority of human genetic deafness is recessively inherited, characterisation of recessive ENU-mutants, such as charlie, will be essential for gaining further insight into the development and functioning of the mammalian auditory system (Kermany et al, 2006;Manji et al, 2012Manji et al, , 2011a2011b;Parker et al, 2010).…”

Differential Expression of Genes within the Cochlea as Defined by a Custom Mouse Inner Ear Microarray

“…It is estimated that over 50% of the several hundred deafness loci are still unknown or uncharacterized. In the mouse, there exist at least 175 spontaneous or genetically manipulated hearing-impaired mutant lines carrying defective genes, with more being identified from the large-scale ENU-mutagenesis screen (Nolan et al 2000;Kiernan et al 2002;Rhodes et al 2003). Studies of these genes and their effects require techniques spanning from behavior to the analysis of unique cell types of the ear and their structureYfunction aspects.…”