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Headbobber: a combined morphogenetic and cochleosaccular mouse model to study 10qter deletions in human deafness
Journal article   Open access   Peer reviewed

Headbobber: a combined morphogenetic and cochleosaccular mouse model to study 10qter deletions in human deafness

Annalisa Buniello, Rachel E Hardisty-Hughes, Johanna C Pass, Eva Bober, Richard J Smith and Karen P Steel
PloS one, Vol.8(2), pp.e56274-e56274
2013
DOI: 10.1371/journal.pone.0056274
PMCID: PMC3572983
PMID: 23457544
url
https://doi.org/10.1371/journal.pone.0056274View
Published (Version of record) Open Access

Abstract

The recessive mouse mutant headbobber (hb) displays the characteristic behavioural traits associated with vestibular defects including headbobbing, circling and deafness. This mutation was caused by the insertion of a transgene into distal chromosome 7 affecting expression of native genes. 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 the cochlear sensory hair cells, the stria vascularis looks severely disorganised, Reissner's membrane is collapsed and no endocochlear potential is detected. Myo7a and Kcnj10 expression analysis show a lack of the melanocyte-like intermediate cells in hb/hb stria vascularis, which can explain the absence of endocochlear potential. We use Trp2 as a marker of melanoblasts migrating from the neural crest at E12.5 and show that they do not interdigitate into the developing strial epithelium, associated with abnormal persistence of the basal lamina in the hb/hb cochlea. We perform array CGH, deep sequencing as well as an extensive expression analysis of candidate genes in the headbobber region of hb/hb and littermate controls, and conclude that the headbobber phenotype is caused by: 1) effect of a 648 kb deletion on distal Chr7, resulting in the loss of three protein coding genes (Gpr26, Cpmx2 and Chst15) with expression in the inner ear but unknown function; and 2) indirect, long range effect of the deletion on the expression of neighboring genes on Chr7, associated with downregulation of Hmx3, Hmx2 and Nkx1.2 homeobox transcription factors. Interestingly, deletions of the orthologous region in humans, affecting the same genes, have been reported in nineteen 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 deletion syndrome.
 Biomarkers - metabolism Chromosome Deletion Deafness - genetics Morphogenesis - genetics Saccule and Utricle - metabolism Genes, Recessive - genetics Down-Regulation Homeodomain Proteins - metabolism Humans Saccule and Utricle - pathology Deafness - physiopathology Basement Membrane - metabolism Basement Membrane - pathology Sequence Homology, Nucleic Acid Deafness - pathology Phenotype Animals Cochlea - metabolism Deafness - metabolism Cochlea - pathology Gene Deletion Mice Chromosomes, Human, Pair 10 - genetics Disease Models, Animal

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