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

Abstract

Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015

GJB2 Mutations Linked to Hearing Loss Exhibit Differential Trafficking and Functional Defects as Revealed in Cochlear-Relevant Cells

“…The expression of Cx43 in the mature organ of Corti appears negligible, however Cx43 is temporally expressed during development of the human and mouse inner ear (Cohen-Salmon et al, 2004;Locher et al, 2015). Hearing loss-linked Cx26 mutants may therefore be co-expressed with Cx43 during the development of the inner ear.…”

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). …”

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

“…Mutations in genes that disrupt the flow of potassium ions through the multilayered stria vascularis, including gap junctions, channels, pumps and transporters, are common causes of hearing loss (Locher et al, 2015). Despite their importance for auditory function, relatively little is known about the development of lateral cochlear duct cells, compared to their sensory counterparts.…”