Cell cycle regulation in hair cell development and regeneration in the mouse cochlea.

Cell cycle inhibitors play important roles in the development of mammalian cochleae. Loss of function of those factors in mice at various developmental stages results in distinct phenotypes characterized by overproduction or loss of cochlear sensory cells. Our recent study showed that acute deletion of the retinoblastoma protein (Rb) induces rapid cell cycle reentry and subsequent loss of postnatal cochlear hair cells in mice. Clearly, these regulators play multiple roles in cell cycle exit and differentiation of hair cell and supporting cell progenitors. They are also crucial in maintenance of postmitotic states and survival of differentiated hair cells and supporting cells. In mammals, lost hair cells cannot be spontaneously replaced, leading to permanent deafness. However, lower vertebrates such as birds and fish can naturally regenerate damaged hair cells from the underlying supporting cells through proliferation and transdifferentiation. Thus, manipulating cell cycle inhibitors in mammalian cochleae could provide a new avenue to restore hearing in deaf people caused by a variety of genetic mutations and environmental insults.