Developmental regulation of planar cell polarity and hair bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics

摘要

Hearing loss is the most common and costly sensory defect in humans, and genetic causes underlie a significant proportion of affected individuals. In mammals, sound is detected by hair cells housed in the cochlea of the inner ear, whose function depends on a highly specialized mechanotransduction organelle, the hair bundle. Understanding the factors that regulate the development and functional maturation of the hair bundle is crucial for understanding the pathophysiology of human deafness. Genetic analysis of deafness genes in animal models, together with complementary forward genetic screens and conditional knock-out mutations in essential genes, have provided great insights into the molecular machinery underpinning hair bundle development and function. In this review, we highlight recent advances in our understanding of hair bundle morphogenesis, with an emphasis on the molecular pathways governing hair bundle polarity and orientation. We next discuss the proteins and structural elements important for hair cell mechanotransduction as well as hair bundle cohesion and maintenance. In addition, developmental signals thought to regulate tonotopic features of hair cells are introduced. Finally, novel approaches that complement classic genetics for studying the molecular etiology of human deafness are presented.