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Development of the Stria Vascularis and Potassium Regulation in the Human Fetal Cochlea: Insights Into Hereditary Sensorineural Hearing Loss

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Development of the Stria Vascularis and Potassium Regulation in the Human Fetal Cochlea: Insights Into Hereditary Sensorineural Hearing Loss Development of the Stria Vascularis and Potassium Regulation in the Human Fetal Cochlea: Insights into Hereditary Sensorineural Hearing Loss Heiko Locher,1,2 John C.M.J. de Groot,2 Liesbeth van Iperen,1 Margriet A. Huisman,2 Johan H.M. Frijns,2 Susana M. Chuva de Sousa Lopes1,3 1 Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 2 Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 3 Department for Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium Received 25 August 2014; revised 2 February 2015; accepted 2 February 2015 ABSTRACT: Sensorineural hearing loss (SNHL) is dynamics of key potassium-regulating proteins. At W12, one of the most common congenital disorders in humans, MITF1/SOX101/KIT1 neural-crest-derived melano- afflicting one in every thousand newborns. The majority cytes migrated into the cochlea and penetrated the base- is of heritable origin and can be divided in syndromic ment membrane of the lateral wall epithelium, and nonsyndromic forms. Knowledge of the expression developing into the intermediate cells of the stria vascula- profile of affected genes in the human fetal cochlea is lim- ris. These melanocytes tightly integrated with Na1/K1- ited, and as many of the gene mutations causing SNHL ATPase-positive marginal cells, which started to express likely affect the stria vascularis or cochlear potassium KCNQ1 in their apical membrane at W16. At W18, homeostasis (both essential to hearing), a better insight KCNJ10 and gap junction proteins GJB2/CX26 and into the embryological development of this organ is GJB6/CX30 were expressed in the cells in the outer sul- needed to understand SNHL etiologies. We present an cus, but not in the spiral ligament. Finally, we investi- investigation on the development of the stria vascularis in gated GJA1/CX43 and GJE1/CX23 expression, and the human fetal cochlea between 9 and 18 weeks of gesta- suggest that GJE1 presents a potential new SNHL associ- tion (W9–W18) and show the cochlear expression ated locus. Our study helps to better understand human cochlear development, provides more insight into multi- Correspondence to: H. Locher ([email protected]) or S. M. ple forms of hereditary SNHL, and suggests that human Chuva de Sousa Lopes ([email protected]) hearing does not commence before the third trimester of Contract grant sponsor: Netherlands Organisation for Scientific pregnancy. VC 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: Research (NWO, ASPASIA 015.007.037, www.nwo.nl/aspasia. 1219–1240, 2015 Contract grant sponsor: Interuniversity Attraction Poles (IAP, P7/07). Keywords: human; sensorineural hearing loss; develop- Contract grant sponsor: Stichting Het Heinsius-Houbolt Fonds, ment; stria vascularis; melanocytes the Netherlands (to H.L.). Additional Supporting Information may be found in the online version of this article. This is an open access article under the terms of the Creative INTRODUCTION Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. According to recent estimates of the World Health Ó 2015 The Authors Developmental Neurobiology Published by Organization, more than 5% of the world’s total pop- Wiley Periodicals, Inc. ulation suffer from some form of disabling hearing Published online 28 February 2015 in Wiley Online Library (wileyonlinelibrary.com). loss (WHO, 2014). A large part of this hearing loss is DOI 10.1002/dneu.22279 of sensorineural nature, making sensorineural hearing 1219 1220 Locher et al. loss (SNHL) the most prevalent sensorineural disor- larized and consists of three layers of distinct cell der in humans. SNHL is also the most common con- types: the marginal cells, the intermediate cells (mela- genital disorder, with a prevalence of 1 in every 1000 nocytes), and the basal cells (Kimura and Schuknecht, newborns in the UK and the Netherlands (with a 1970; Hilding and Ginzberg, 1977). It is generally bilateral hearing loss 40 dB (NHSP, 2011; van der accepted that the depolarizing K1 flow causing hair Ploeg et al., 2012)). Of these, over two-thirds can be cell activation in the organ of Corti is recycled back attributed to genetic factors. Hereditary SNHL can be to the stria vascularis via the epithelial lining of the classified in syndromic (25%) and nonsyndromic cochlear duct and the spiral ligament fibrocytes, and/ (75%) forms (Morton and Nance, 2006). or through the perilymph, as depicted in Figure 1. To Examples of syndromic SNHL include Pendred’s maintain the endocochlear potential, this recycling syndrome ([MIM 274600, www.omim.org/], combin- system requires a specific distribution of cochlear cell ing hearing loss and goiter (Pendred, 1896; Bizha- types as well as selective ion channels and gap- nova and Kopp, 2010)), Waardenburg syndrome junctions (Zdebik et al., 2009; Adachi et al., 2013). [WS; hearing loss and pigmentation abnormalities Therefore, it is not surprising that many gene (Waardenburg, 1951; Pingault et al., 2010)] and Jer- mutations causing SNHL either result in functional vell and Lange-Nielsen syndrome ([MIM 220400 and changes of the ion channels involved in K1 homeo- MIM 612347], hearing loss and cardiac symptoms stasis or cause an abnormal cellular morphology in (Jervell and Lange-Nielsen, 1957)). In nonsyndromic the cochlea. Although progress has been made in SNHL, associations with obvious abnormalities of identifying the genes responsible for SNHL in the external ear or symptoms other than hearing loss humans, knowledge on their actual expression in the cannot be found, but the heterogeneity of loci and human cochlea is limited and only a few studies have genes is high: over 130 loci have been mapped and investigated the morphological development of the over 60 different genes have been implicated pres- stria vascularis in the human fetal cochlea (Lavigne- ently (van Camp and Smith). Nonsyndromic forms Rebillard and Bagger-Sjob€ €ack, 1992; Bibas et al., are grouped in autosomal dominant (DFNA), autoso- 2000). In this article, we address both aspects, focus- mal recessive (DFNB), X-linked (DNFX) and mitro- sing on the embryonic development of the lateral chondrial subtypes. The most commonly affected wall in the human fetal cochlea. We show the expres- gene causing nonsyndromic hearing loss (both in sion profiles of several genes involved in syndromic autosomal recessive DFNB1A [MIM 220290] and in and nonsyndromic SNHL (Table 1) between 9 and 18 autosomal dominant DFNA3A [MIM 601544]) is gap weeks of gestation (W9–W18). More specifically, we junction beta 2 (GJB2, [MIM 121011]), the gene have investigated the development of the different encoding the connexin 26 protein (CX26) (Kelsell cell types in the stria vascularis and studied the et al., 1997; Denoyelle et al., 1997). Depending on expression of K1-regulating and gap junction pro- the studied population, 20–50% of all recessive non- teins. Together, our data give insight in hereditary syndromic SNHL cases can be attributed to a muta- SNHL and provide a basis for K1-recycling models tion in GJB2 (Hilgert et al., 2009a; Linden Phillips in the human cochlea. et al., 2013). For a comprehensive overview of other affected genes, we refer to recent reviews (Hilgert et al., 2009b; Angeli et al., 2012; Shearer and Smith, METHODS 2012; Smith et al., 2014; Stelma and Bhutta, 2014). In SNHL, the disorder lies either in the cochlea Tissue Samples itself or in any of the retrocochlear auditory struc- tures. Cochlear hair cells are responsible for convert- Human fetal cochleas were collected from tissues obtained ing sound into electrical signals that travel to the by elective abortion (healthy subjects, no medical indica- brainstem via the cochlear nerve (Hudspeth, 1989). tion) using vacuum aspiration. Prior to the procedure, Hair cell function depends on the endocochlear poten- obstetric ultrasonography was used to determine the gesta- tial, a positive extracellular potential (80–100 mV tional age in weeks and days. Of all collected cochleas, we relative to perilymph) in the endolymph of the coch- discarded those which where mechanically damaged or showed marked tissue degeneration, upon inspection by lear duct (or scala media), generated by an unusually 1 light-microscopy. Cochleas of the following gestational high concentration of potassium ions (K ) (Smith ages were collected and used: W9, W9.1, W10.4 (23), et al., 1954). These ions are secreted into the endo- W12 (23), W12.2, W14 (23), W16 (23), W18 (33). The lymph by specialized cells within the stria vascularis, cochleas were obtained in PBS, fixed in 4% paraformalde- located in the lateral wall of the cochlear duct hyde in PBS overnight at 4C, decalcified and embedded in (Patuzzi, 2011). The stria vascularis is highly vascu- paraffin as previously described (Locher et al., 2013). The Developmental Neurobiology Development of the Human Stria Vascularis 1221 use of human fetal material was approved by the Medical Ethical Committee of the Leiden University Medical Cen- ter (protocol 08.087). Informed written consent was obtained in accordance with the WMA Declaration of Hel- sinki guidelines. Immunohistochemistry The cochleas were cut in 5 or 10 lm thick sections in the sagittal plane using a RM2255 microtome (Leica). Deparaf- finization and immunohistochemistry were carried out as previously described (Locher et al., 2013). Briefly, antigen
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