Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System

Abstract

Summary: Utricular hair cells (HCs) are mechanoreceptors required for vestibular function. After damage, regeneration of mammalian utricular HCs is limited and regenerated HCs appear immature. Thus, loss of vestibular function is presumed irreversible. Here, we found partial HC replacement and functional recovery in the mature mouse utricle, both enhanced by overexpressing the transcription factor Atoh1. Following damage, long-term fate mapping revealed that support cells non-mitotically and modestly regenerated HCs displaying no or immature bundles. By contrast, Atoh1 overexpression stimulated proliferation and widespread regeneration of HCs exhibiting elongated bundles, patent mechanotransduction channels, and synaptic connections. Finally, although damage without Atoh1 overexpression failed to initiate or sustain a spontaneous functional recovery, Atoh1 overexpression significantly enhanced both the degree and percentage of animals exhibiting sustained functional recovery. Therefore, the mature, damaged utricle has an Atoh1-responsive regenerative program leading to functional recovery, underscoring the potential of a reprogramming approach to sensory regeneration. : The mature mouse utricle, which detects linear acceleration, displays limited regeneration, but whether function returns is unknown. Sayyid et al. show that regenerated hair cells appear and mature over months, resulting in a limited, unsustained functional recovery. Atoh1 overexpression enhances regeneration and leads to a sustained recovery of vestibular function. Keywords: utricle, hair cell, vestibular, sensory, regeneration, proliferation, Atoh1, vestibular evoked potential