Neurosensory development and cell fate determination in the human cochlea

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.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…3(B)]. We recently observed additional expression throughout the human fetal cochlear duct epithelium (Locher et al, 2013) and in all peripheral glial cells (Locher et al, 2014). Although it is likely that melanocytes play a major role in SNHL in WS or KS due to SOX10 mutations, it cannot be excluded that other SOX10+ cell types in the cochlea are involved as well.…”

“…This implies that the endocochlear potential cannot be generated at this stage and, therefore, that the human fetus at W18 is still unable to hear. Although W20 has been proposed by us (Locher et al, 2013; Locher et al, 2014) and others (Pujol et al, 1991; Pujol and Lavigne‐Rebillard, 1995; Bibas et al, 2008) as the onset of human hearing based on the maturation of the organ of Corti and the cochlear nerve, it is more likely that hearing commences a few weeks later, which is in line with otoacoustic emission measurements (Chabert et al, 2006) and auditory brainstem responses in preterm infants (Lary et al, 1985; van Straaten et al, 2001). …”

“…Cochleas of the following gestational ages were collected and used: W9, W9.1, W10.4 (2×), W12 (2×), W12.2, W14 (2×), W16 (2×), W18 (3×). The cochleas were obtained in PBS, fixed in 4% paraformaldehyde in PBS overnight at 4°C, decalcified and embedded in paraffin as previously described (Locher et al, 2013). The use of human fetal material was approved by the Medical Ethical Committee of the Leiden University Medical Center (protocol 08.087).…”

“…Deparaffinization and immunohistochemistry were carried out as previously described (Locher et al, 2013). Briefly, antigen retrieval was performed (see below) and sections were consecutively incubated with primary and secondary antibodies diluted in blocking solution consisting of 1% bovine serum albumin (Sigma‐Aldrich) and 0.05% Tween‐20 (Promega) in PBS.…”

In Vitro Models of GJB2-Related Hearing Loss Recapitulate Ca2+ Transients via a Gap Junction Characteristic of Developing Cochlea

“…CX26 and CX30 form heteromeric and heterotypic channels in most of the cochlear gap junction plaques (GJPs) (Sun et al., 2005) and in in vitro experiments (Yum et al., 2007). Recently, expression of various transcription factors and other proteins in human developmental fetal cochleae from gestational weeks 9–22 were investigated using immunohistochemistry (Locher et al., 2013, Locher et al., 2014), and it has been found that the expression of CX26 and CX30 is detectable in the outer sulcus cells at 18 weeks of gestation (Locher et al., 2015). …”