Nucleolin is essential for hair cell stereocilia maintenance and auditory function in mice

As the mechanosensitive sensory cells in the inner ear, hair cells are characterized by their apical, F-actin-filled stereocilia. The stereocilia are organized into a staircase-like pattern with rows of increasing height. The development and maintenance of stereocilia are tightly regulated, and deficits in this process usually lead to hearing loss. Recently, our group reported that RNA-binding proteins (RBPs), such as RBM24 and ESRP1, play essential roles in the inner ear hair cells. In the present work, we show that nucleolin (NCL), a highly conserved RBP, is required for stereocilia maintenance in inner ear hair cells. Ncl knockout leads to progressive stereocilia degeneration in the outer hair cells in a basal-to-apical gradient. Meanwhile, Ncl knockout results in progressive stereocilia fusion in the inner hair cells in an apical-to-basal gradient. As a result, these stereocilia deficits lead to hair cell loss and eventually cause hearing loss in Ncl conditional knockout mice. RNA-sequencing analysis identified several genes for which the mRNA level is affected by Ncl knockout. Among them are Espnl and Ptprq, which have been shown to play essential roles in stereocilia development and/or maintenance. Further investigations confirmed that NCL could directly bind to Espnl and Ptprq mRNAs, and that NCL could increase the stability of Espnl and Ptprq mRNAs. Together, our data demonstrate that NCL plays essential roles in stereocilia maintenance by regulating the stability of its target mRNAs.