Lateral inhibition and mechanical forces regulate vestibular system embryonic development

The vestibular system is in charge of keeping our balance by sensing acceleration and gravitation. Each of its sensory organs consists of an alternating pattern of sensory hair cells (HCs) and non-sensory supporting cells (SCs). Many non-mammalian species have the capability to regenerate lost HCs by the differentiation of nearby SCs. Unfortunately, mammals lose this capability in an early developmental stage, making us vulnerable to vestibular dysfunction and balance disorders. A possible reason for this difference might be the different mechanical properties of the mammalian versus the non-mammalian systems. Recent studies have shown that inner ear development is not only regulated by biochemical-signaling, as previously thought, but also by mechanical forces. However, the exact way in which the coordination between these two mechanisms regulates the vestibular system’s development is yet unknown. In this research we developed a live imaging assay of vestibular system explants. Using double transgenic mice, we track the cells’ apical morphology and differentiation. Our preliminary results show that HC patterning is a continuous process involving coordinated differentiation, division, and delamination events. We show that HC ablation promotes differentiation of nearby SCs, both for embryos and newborns. A mathematical model that includes a feedback between Notch mediated lateral inhibition and mechanical forces can capture the main observations. Our findings provide a first step towards elucidating the mechanical and regulatory factors affecting vestibular system development and HC regeneration. In addition, they may contribute to developing treatments for balance disorders, by inducing HC regeneration at post-natal stages.