Journal Article

Helios is a key transcriptional regulator of outer hair cell maturation

Matern, Maggie S., Brown, Steve D. M., Trent, Graham, Bowl, Michael R., Elkon, Ran, Milon, Beatrice, Parker, Andrew, Hertzano, Ronna, Chessum, Lauren, Esapa, Christopher T., Johnson, Stuart L., Wells, Sara, Song, Yang, Codner, Gemma, Prescott, Jack, Frolenkov, Gregory I., McMurray, Mark, Kelley, Matthew W., Ogawa, Yoko, Dragich, Abigail K., Kelly, Michael C., Driver, Elizabeth C., Marcotti, Walter

2018

Overview

The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning 1 . Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2 cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm . Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity. Ikzf2 , which encodes the transcription factor Helios, is identified as a crucial regulator of gene expression in maturing cochlear outer hair cells, and overexpression of Ikzf2 in inner hair cells induces prestin expression and electromotility.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Age / Animals / Base Sequence / Bioinformatics / Biomarkers - metabolism / Cochlea / DNA-Binding Proteins - metabolism / Ectopic expression / Female / Gene expression / Gene Expression Regulation, Developmental - genetics / Gene mutation / Genes / Genetic aspects / Genomes / Hair / Hair cells / Hair cells (Sensory receptors) / Hair Cells, Auditory, Outer - cytology / Hair Cells, Auditory, Outer - metabolism / Hearing loss / Humanities and Social Sciences / Letter / Male / Maturation / Mice / Mice, Inbred C57BL / multidisciplinary / Mutation / Neurophysiology / Outer hair cells / Physiological aspects / Point mutation / Proteins / Science / Science (multidisciplinary) / Transcription (Genetics) / Transcription factors / Transcription Factors - metabolism / Transcription, Genetic / Transcriptome - genetics