Role of Rho-GTPases in Regulation of the Hearing and Balance System

Abstract

　The inner ear consists of the cochlea and vestibule, both containing sensory hair cells, which possess strictly regulated actin organization to conduct sensitive mechanoelectrical transduction. Rho-GTPase is a family of small GTPases, known to play key roles in actin regulation. Cdc42 and Rac (Rac1, Rac2, Rac3) are major members of Rho-GTPase family and we have previously confirmed the expression of Cdc42, Rac1 and Rac3 in cochlear sensory epithelia. Recently we studied the function of Cdc42 and Rac in inner ears and the cerebellum using a gene-targeting strategy. We developed a Cdc42-conditional knock-out mouse (Cdc42-CKO mouse) using the Cre-loxP system under an Atoh1 promotor to establish a model of hair cell-specific deletion of Cdc42. The Cdc42-CKO mouse showed progressive hearing loss associated with hair bundle degeneration, structural abnormality of the apical cell junction and hair cell loss. On the other hand, the Rac1-CKO mouse, Rac3-KO mouse and their crossbred Rac1/Rac3 double knock-out (Rac1/3-DKO) mouse did not show this hearing phenotype. These data indicated that Cdc42 is essential for maintaining hearing function by regulation of actin dynamics in the hair cells, whereas Rac molecules are not necessary for hair cell function. Both the Cdc42-CKO mouse and Rac1/3-DKO did not show the vestibular phenotype, suggesting the existence of other Rho-GTPases compensating for the function of Cdc42 in the vestibular organ. Moreover, the Rac1/3-DKO mouse showed an ataxic gait and cerebellar hypoplasia, although these phenotypes are much more subtle in the Rac1-KO mouse and not observed in the Rac3-KO mouse. We found hypoplasia of the inner granular layer and dysfunction of neurite growth in the Rac1/3-DKO mouse, suggesting a compensatory function of Rac1 and Rac3 in the neurite extension and cellular migration of cerebellar granular cells. Further studies are needed to explore the function and compensatory mechanism of the Rho-GTPase family in the inner ears and cerebellum to elucidate fully the molecular regulation of the hearing and balance system.