Neurosensory development and cell fate determination in the human cochlea

Heiko Locher,John Cmj De Groot,Liesbeth Van Iperen,Susana M Chuva De Sousa Lopes,Margriet A Huisman,Johan Hm Frijns

doi:10.1186/1749-8104-8-20

Abstract

BackgroundHearing depends on correct functioning of the cochlear hair cells, and their innervation by spiral ganglion neurons. Most of the insight into the embryological and molecular development of this sensory system has been derived from animal studies. In contrast, little is known about the molecular expression patterns and dynamics of signaling molecules during normal fetal development of the human cochlea. In this study, we investigated the onset of hair cell differentiation and innervation in the human fetal cochlea at various stages of development.ResultsAt 10 weeks of gestation, we observed a prosensory domain expressing SOX2 and SOX9/SOX10 within the cochlear duct epithelium. In this domain, hair cell differentiation was consistently present from 12 weeks, coinciding with downregulation of SOX9/SOX10, to be followed several weeks later by downregulation of SOX2. Outgrowing neurites from spiral ganglion neurons were found penetrating into the cochlear duct epithelium prior to hair cell differentiation, and directly targeted the hair cells as they developed. Ubiquitous Peripherin expression by spiral ganglion neurons gradually diminished and became restricted to the type II spiral ganglion neurons by 18 weeks. At 20 weeks, when the onset of human hearing is thought to take place, the expression profiles in hair cells and spiral ganglion neurons matched the expression patterns of the adult mammalian cochleae.ConclusionsOur study provides new insights into the fetal development of the human cochlea, contributing to our understanding of deafness and to the development of new therapeutic strategies to restore hearing.

Highlights

Hearing depends on correct functioning of the cochlear hair cells, and their innervation by spiral ganglion neurons
The human prosensory domain is SOX2-positive To determine whether a prosensory domain exists during human development, we investigated the expression of SOX2 at W10.4, a stage when the cochlear duct epithelium showed no clear morphological hair cell specification (Figure 1A)
Nuclear SOX2 expression was already restricted to the human prosensory domain (Figure 1B) and no expression was visible in other parts of the cochlear duct, except for cytoplasmic SOX2 expression in the lateral wall of the cochlear duct epithelium (Figure 1B, asterisk)

Summary

Introduction

Hearing depends on correct functioning of the cochlear hair cells, and their innervation by spiral ganglion neurons. We investigated the onset of hair cell differentiation and innervation in the human fetal cochlea at various stages of development. The cochlea houses two of the main cell types responsible for hearing: the hair cells and the spiral ganglion neurons (SGNs). SGNs project to both IHCs and OHCs until 6 to 7 days after birth, when a clear distinction between type I and type II ganglion neurons takes place, just prior to the onset of hearing (post-natal week 2) [13,14]. Penetration of the SGN neurites into the cochlear neuroepithelium has been observed earlier than the first differentiation of hair cells by electron microscopy [5]. The separation of type I and type II SGNs has not been investigated in humans

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