Restoring balance: how axolotls regenerate otoconia for gravity sensing

Gravity deeply impacts all life on Earth. Organisms sense its directionality and use it for orientation. In tetrapods, the gravitational sense relies on biomineral crystals, known as otoconia, in our inner ear. Their movement is detected by sensory cells, transduced into a neural output, and interpreted by the brain. Deterioration of the otoconia can cause severe balance issues, contributing to diseases collectively referred to as vestibular disorders. Yet, the processes driving both otoconia formation and degradation remain unclear. Limitations in diagnosis of balance disorders in humans stem from the inaccessibility of the inner ear for studying which components are functioning deficiently. In this context there is a need to develop models of vestibular function, disease and restoration. The ultimate goal of OTOREG is to uncover fundamental mechanisms underlying gravity sensation, using the axolotl as a model of regeneration and balance disorders.The morphology of the salamander inner ear is strikingly similar to mammals and my preliminary data indicates that removal of otoconia leads to a balance disorder phenotype. Otoconia then regenerate in the axolotl, restoring correct swimming behaviour and providing a functional readout. This system thus permits a holistic, multilevel approach to understand gravity sensation: I) At the biomaterial level, using structural methods to investigate crystal development and regeneration; II) at the molecular and cellular level, to characterize the genes and cells that drive the formation of the sensory apparatus; and III) at the organismal level, using the behavioural readout to test compounds which might contribute to the degeneration or restoration of otoconia. This detailed understanding of the gravity sensation organ can provide a platform for studying and developing therapeutical approaches for balance disorders to improve people’s quality of life, as well as to probe the fascinating biology of our most ancient sense.