Role of Cytoplasmic Actin Isoforms in the Inner Ear

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DESCRIPTION (provided by applicant): Actin is one of the most abundant proteins in nature and plays essential roles in almost every cellular function including muscle contraction, cell migration, vesicle trafficking, and polarized growth. Two cytoplasmic actin isoforms, ¿cyto- and ?cyto-actin, are ubiquitously expressed. Although encoded by separate genes, these cytoplasmic actin isoforms vary at only 4 of 375 amino acid residues; however, these small sequence differences are conserved between birds and mammals, suggesting that ¿cyto-- and ?cyto-actin nave distinct cellular functions. Consistent with this idea, the cellular localization of ¿cyto-- and ?cyto-actin differ, which is thought to contribute to cell polarization. Additionally, some ?cyto-actin mutations lead to progressive deafness in humans, indicating an essential cellular role for this isoform that cannot be filled by ¿cyto-actin. Although impressive gains have been made in understanding how actins are regulated by other proteins, the distinct functions of ¿- and ?cyto--actin remain poorly understood. The goals of this fellowship include elucidating the specific functions of ¿cyto- and ?cyto--actin in the mammalian inner ear. Preliminary evidence suggests that ?cyto--actin deficient mice display progressive hearing loss. A ¿cyto-actin-deficient mouse will be generated to allow for a comparison of the effect ¿cyto- and ?cyto-actin deficiency on auditory physiology. Additionally, the structure and function of polarized inner ear cells in both models will be analyzed by both light and electron microscopy to understand the cellular mechanism underling changes in hearing. This fellowship will contribute to improving public health by furthering understanding of the distinct contributions of ¿cyto- and ?cyto--actin to normal cell biology. Additionally, progressive deafness caused by mutation of the human ?cyto-actin 9ene is Paralleled by the phenotype of the ?cyto--actin deficient mouse, characterization of which will likely provide insight into the pathomechanism of this form of human deafness.