Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium.

Ting Zhang,Pascal Maire,Pin-Xian Xu,Jinshu Xu

doi:10.1371/journal.pgen.1006967

Abstract

The organ of Corti in the cochlea is a two-cell layered epithelium: one cell layer of mechanosensory hair cells that align into one row of inner and three rows of outer hair cells interdigitated with one cell layer of underlying supporting cells along the entire length of the cochlear spiral. These two types of epithelial cells are derived from common precursors in the four- to five-cell layered primordium and acquire functionally important shapes during terminal differentiation through the thinning process and convergent extension. Here, we have examined the role of Six1 in the establishment of the auditory sensory epithelium. Our data show that prior to terminal differentiation of the precursor cells, deletion of Six1 leads to formation of only a few hair cells and defective patterning of the sensory epithelium. Previous studies have suggested that downregulation of Sox2 expression in differentiating hair cells must occur after Atoh1 mRNA activation in order to allow Atoh1 protein accumulation due to antagonistic effects between Atoh1 and Sox2. Our analysis indicates that downregulation of Sox2 in the differentiating hair cells depends on Six1 activity. Furthermore, we found that Six1 is required for the maintenance of Fgf8 expression and dynamic distribution of N-cadherin and E-cadherin in the organ of Corti during differentiation. Together, our analyses uncover essential roles of Six1 in hair cell differentiation and formation of the organ of Corti in the mammalian cochlea.

Highlights

In response to a variety of signals, the prosensory progenitors in the floor of the mammalian cochlear duct enter terminal mitosis and differentiate into a mosaic of mechanosensory hair cells interdigitated with several subtypes of nonsensory supporting cells, including inner border, inner phalangeal, inner and outer pillar and three rows of Deiters’ cells aligned in a medial-to-lateral direction
Auditory sensory hair cells and surrounding supporting cells are derived from common prosensory progenitors, which undergo rearrangements through intercalation to achieve extension and establish the mosaic structure between hair and supporting cells
Through temporal deletion of Six1 in the developing cochlea, we found that Six1 activity is crucial for proper hair cell fate specification and for the regulation and maintenance of the spatiotemporal pattern of Sox2, Fgf8 and E- and N-cadherins during differentiation

Summary

Introduction

In response to a variety of signals, the prosensory progenitors in the floor of the mammalian cochlear duct enter terminal mitosis and differentiate into a mosaic of mechanosensory hair cells (one row of inner and three rows of outer hair cells) interdigitated with several subtypes of nonsensory supporting cells, including inner border, inner phalangeal, inner and outer pillar and three rows of Deiters’ cells aligned in a medial-to-lateral direction. The prosensory progenitor cells proliferate to expand, and after reaching a defined number, exit the cell cycle from apex toward base between E12.5 to E14.5 to form a four- to five-cell layered non-proliferating precursor domain–the primordial organ of Corti, which is marked by expression of p27Kip1 [2, 3] Soon after their cell cycle exit, the precursors initiate cell-type specific terminal differentiation near the base toward apex from E14.5 and undergo unidirectional cellular intercalation movement called convergent extension to form the two layers of epithelial cells, a lumenal layer of hair cells and a basal layer of supporting cells [3,4,5]. Despite extensive research on identifying factors that are important for hair cell morphogenesis, how these individual factors interact to generate different types of epithelial cells with distinct shapes and functions in the organ of Corti is still poorly understood It is even more unclear how these interactions are precisely regulated to induce robust epithelial morphogenesis of the cochlea

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