Understanding the Role of Espin-Like (ESPNL) in Auditory Stereocilia Development and Maintenance

Abstract

Hair cells are the fundamental unit of hearing, as they transform the mechanical force of sound waves into electrical signals through a process called mechanotransduction (MET). Stereocilia are large, actin based, microvilli-like “hairs” that arise from the apical surface of the cell. Approximately 50-150 stereocilia are organized into a bundle made by three rows of graded heights, resembling a staircase, the tallest being called row 1 and the shortest row 3. The stereocilia are connected from the tip of the shorter stereocilium to the shaft of the taller stereocilium by a connection known as a tip-link. When acted upon by sound, stereocilia deflect toward row 1, allowing tip-links to pull open the gated MET channels at the tips of row 2 and 3. The dimensions of stereocilia are tightly regulated by actin binding proteins to operate in this highly precise manner. When stereocilia dimensions become dysregulated, the bundle cannot be efficiently stimulated by sound and hearing loss occurs. Dysregulation is exacerbated by age, as damage accumulates over the lifespan. A problem humans face is that mammalian hair cells are terminally differentiated and must last many decades. As the world’s population is living longer and industrialization is increasing the sound levels of daily life, further research is necessary to develop stereocilia loss prevention interventions and/or methods for hair cell regeneration. Mechanotransduction is not only the primary function of hair cells but also an influence on actin regulation in stereocilia development, maintenance, and seemingly hair cell viability. In this work we study two similar actin binding protein families, ESPN and ESPNL, to understand their roles in stereocilia development. Our EspnlD20 /D20 mutant exhibited a common age-related hearing loss phenotype characterized by progressive row 2 dysregulation and subsequent loss. We also identified a novel isoform of ESPNL that responds to MET. Lastly, we attempted to further study progressive transducing stereocilia degeneration and its effects on hair cell health through a harmonin mutant which exhibits weakened tip-link complexes. This work furthers our understanding of stereocilia development and moves us closer to a model to analyze the critical role MET plays in auditory cell health.