The Glutaredoxin-like Cysteine-rich Family of Genes, Grxcr1 and Grxcr2, in Stereocilia Development and Function.

Auditory Genetics;Genetics;Health Sciences;Human Genetics

Avenarius, Matthew R.Weisman, Lois ;

University of Michigan

关键词: Auditory Genetics;    Genetics;    Health Sciences;    Human Genetics;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/91447/avenarim_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Grxcr1 encodes an evolutionarily conserved cysteine-rich protein with sequence similarity to the glutaredoxin family of proteins.Mutations in this Grxcr1 are associated with deafness and vestibular dysfunction in the pirouette mouse, a model for human deafness segregating at the DFNB25 locus. In this thesis, I characterize spontaneous loss of function mutations in Grxcr1 and a paralogous gene, Grxcr2, in vivo, and explore structure-function relationships between genes to provide insight into their functions in the inner ear. Mice homozygous for null alleles of Grxcr1 exhibit abnormally thin stereocilia on the apical surface of sensory cells in the inner ear, indicating a role for this gene in the control of stereocilia dimensions.Despite defects in stereocilia maturation, sensory hair cells exhibit relatively normal mechanotransduction at early postnatal time points. The vertebrate specific paralog, Grxcr2, encodes a proteinthat is localized to stereocilia of sensory cells in the cochlea and vestibular organs, similar to GRXCR1. Generation and analysis of a targeted mutation of mouse Grxcr2 indicated a similar requirement for this gene in the normal maturation of stereocilia bundles and in auditory function.Mice homozygous for the Grxcr2 mutation exhibited severe hearing loss associated with abnormal stereocilia bundle orientation and organization. Later onset hearing loss in mice homozygous for the Grxcr2 hypomorphic allele suggests that this gene may also be required to maintain auditory function in the mature cochlea. The different stereocilia morphologies identified in Grxcr1 and Grxcr2 mutants and the lack of an overt vestibular phenotype in Grxcr2 mutants, are consistent with distinct roles for these genes during inner ear development. Structure-function analysis of GRXCR1 and GRXCR2 indicated a conserved role for the N-terminus in localization of these proteins to actin filament-rich structures and for the C-terminal Cysteine-rich domain in mediating multimer formation. These studies suggest a model in which multimeric complexes of GRXCR1 and GRXCR2 play a local role to coordinate proper stereocilia development.