| description |
The recessive mouse mutant headbobber (hb) displays the characteristic behavioural traits associated with vestibular defects including headbobbing, circling and deafness. This mutation was identified in a line carrying an integrated transgene and the phenotype mapped to distal chromosome 7. We show that the inner ear of hb/hb mutants lacks semicircular canals and cristae, and the saccule and utricle are fused together in a single utriculosaccular sac. Moreover, we detect severe abnormalities of their cochlear sensory cells, stria vascularis looks severely disorganised, Reissner’s membrane is collapsed and no endocochlear potential was detected. Myo7a and Kcnj10 expression analysis showed a lack of intermediate cells in hb/hb stria vascularis, which explains the absence of endocochlear potential. We used Trp2 as a marker of melanoblasts migrating from the neural crest at E12.5 and showed that they do not interdigitate into the developing strial epithelium, associated with abnormal persistance of the basal lamina in the hb/hb cochlea. After having performed array CGH as well as an extensive expression analysis of candidate genes in the headbobber region on hb/hb and littermate controls, we can conclude that the headbobber combined morphogenetic and cochleosaccular phenotype is caused by an addition of different effects: 1) effect of a 600kb deletion on distal Chr7, with the loss of a few protein coding genes with interesting expression patterns and unknown function in the inner ear; 2) indirect, long range effect of the deletion on the expression of neighboring genes on Chr7, associated with downregulation of Hmx genes. Interestingly, deletions of the homologous region in humans have been reported in a number of patients with common features including sensorineural hearing loss and vestibular problems. Therefore, we propose that headbobber is a useful model to gain insight into the mechanisms underlying deafness in human 10qter deletions. |