Training and aging modulate the loss‐of‐balance phenotype observed in a new ENU‐induced allele of Otopetrin1

Abstract

Background information. The sensing of head movement in mammals depends upon the vestibular endorgan of the inner ear, a complex structure made up of the semicircular canals and otoliths. Due to the similarity between the human and mouse vestibular apparatus, the analysis of mutant mouse is a valuable strategy aiming to identify genes involved in the control of balance and movement.Results. In the course of a genome-wide chemical-mutagenesis programme, we isolated a recessive mutation, named ied (inner ear defect), which induced a severe loss-of-balance. A detailed phenotypic analysis of the mutant mice demonstrates that the balance impairment does not affect the motor activity and can be rescued, in part, by training, despite a complete agenesis of otoconia in the utricule and the saccule of the inner ear. Molecular characterization of the ied mutation revealed a transversion that affects the splicing of the second exon of the Otopetrin1 gene located on mouse chromosome 5. The consequence of such a mutation leads to a disruption of the transcription of the gene.Conclusions. The identification of the ied knock-down allele strengthens the role of the Otopetrin1 in the sensing of balance. Moreover, the rescue of the ied mutant phenotype in specific behavioural tasks confirmed that other sensory inputs or neural plasticity can compensate, to some extent, for the loss-of-balance. In the future, the ied mutant mice might be helpful to study the genetic control of the compensation strategies developed by organisms to counteract balance defects.

Osteopontin is not Critical for Otoconia Formation or Balance Function

“…There was a nearly fourfold increase in latencies on the rotorod on day 4 compared to day 1 (pG0.001), demonstrating normal synaptic potentiation of vestibular neurons, proprioceptors, or locomotor control centers. Although central compensation can potentially mask peripheral deficits (Rampello and Drago 1999;Dubois et al 2002;Besson et al 2005;Bothe et al 2005), concurrent tests with otoconia mutants show that the learned improvement actually differentiates further the normal and imbalance behaviors because the mutants improved less after training (Zhao et al FIG. 4.…”

Otoconin-90 deletion leads to imbalance but normal hearing: A comparison with other otoconia mutants

“…peripheral inputs and central integration), but can also specifically reveal the behavioral outcome of a particular lesion when the lesion is known to be localized to a single organ or system. Severe abnormalities in the gravity receptor organ often lead to abnormal air-righting reflexes, irregular and wider gaits, compromised ability to swim or shortened stay on the rotorod (Trune and Lim, 1983;Ying et al, 1999;Rampello and Drago, 1999;Hamm, 2001;Jones et al, 2004;Besson et al, 2005). We assessed the grip-strengths of the animals to rule out neuromuscular weakness as a possible secondary outcome of the vestibular sensory deficits.…”

“…The mice occasionally have a few giant otoconia in the saccule . Other Otop1 mutants include the ethylnitrosourea-induced alleles Otop1 mlh (Hurle et al, 2003) and Otop1 ied (Besson et al, 2005).The present study aims to compare the behavioral outcome of otoconia deficiencies in Oc90 null mice with the amount of sensory input relayed by the gravity receptor organ using VsEPs, a noninvasive method that directly measures the sensitivity of the gravity receptor organ Jones, 2008 …”

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

“…Similar to the phenotypes seen in het and hslt mice, the tilted (tlt), mergulhador (mlh), and inner ear defect (ied) mice carry mutations in the novel multi-transmembrane domain protein, Otopetrin 1 (Otop1), resulting in nonsyndromic otoconial agenesis and a severe balance disorder in mice (Besson et al, 2005;Hurle et al, 2003;Ornitz et al, 1998). The zebrafish otop1 orthologue is a highly conserved gene that is essential for otolith initiation as seen in both morphant otop1 fish and in the backstroke mutant (Hughes et al, 2004;Sollner et al, 2004).…”