Transcript Profiles of Stria Vascularis in Models of Waardenburg Syndrome

Abstract

Background. Waardenburg syndrome is an uncommon genetic condition characterized by at least some degree of congenital hearing loss and pigmentation deficiencies. However, the genetic pathway affecting the development of stria vascularis is not fully illustrated. Methods. The transcript profile of stria vascularis of Waardenburg syndrome was studied using Mitf-M mutant pig and mice models. Therefore, GO analysis was performed to identify the differential gene expression caused by Mitf-M mutation. Results. There were 113 genes in tyrosine metabolism, melanin formation, and ion transportations showed significant changes in pig models and 191 genes in mice models. In addition, there were some spice’s specific gene changes in the stria vascularis in the mouse and porcine models. The expression of tight junction-associated genes, including Cadm1, Cldn11, Pcdh1, Pcdh19, and Cdh24 genes, were significantly higher in porcine models compared to mouse models. Vascular-related and ion channel-related genes in the stria vascularis were also shown significantly difference between the two species. The expression of Col2a1, Col3a1, Col11a1, and Col11a2 genes were higher, and the expression of Col8a2, Cd34, and Ncam genes were lower in the porcine models compared to mouse models. Conclusions. Our data suggests that there is a significant difference on the gene expression and function between these two models.

Modeling of pigmentation disorders associated with MITF mutation in Waardenburg syndrome revealed an impaired melanogenesis pathway in iPS‐derived melanocytes

“…As previous studies described, the MITF mutation caused melanocytes to fail to migrate to the cochlear SV, which resulted in lower endolymphatic potentials (EP) and cochlear hair cell damage in WS pig and mouse models (Chen et al, 2020; Ni et al, 2013; Tachibana et al, 2003). The potassium ions in scala media are produced by intermediate cells, and many potassium channels together with transporters in the lateral wall are involved in maintaining the EP.…”

“…The study successfully differentiated the idiopathic WS patient-specific iPSCs with the MITF mutation into melanocytes in vitro by simulating the natural in vivo development environment. Researchers have conducted an extensive investigation on the pathological mechanism of MITF over the past decade, mainly by using animal models or tool cell lines (Chen et al, 2020;Grill et al, 2013;Hai et al, 2017;Li et al, 2019). These pioneering studies revealed that these MITF mutations mainly impaired melanocyte generation, survival, and function of melanocytes As previous studies described, the MITF mutation caused melanocytes to fail to migrate to the cochlear SV, which resulted in lower endolymphatic potentials (EP) and cochlear hair cell damage in WS pig and mouse models (Chen et al, 2020;Ni et al, 2013;Tachibana et al, 2003).…”

“…The potassium ions in scala media are produced by intermediate cells, and many potassium channels together with transporters in the lateral wall are involved in maintaining the EP. Chen et al (2020) found that the number of genes related to ion transport had decreased expression in the SV transcriptome data regarding MITF mutant pig and mouse models, indicating that MITF can affect auditory development and maintain the EP in the cochlea.…”

“…Based on clinical findings, WS patients with MITF mutations usually show complete expression of possible symptoms, such as severe congenital SNHL, extensive skin hypopigmentation, and complete heterochromia iridum (Song et al, 2016;Wang et al, 2018Wang et al, , 2021. Despite the comprehensive investigation in animal models, the pathogenic mechanism of mutated MITF is still poorly described in humans (Chen et al, 2020;Du et al, 2019;Ni et al, 2013;Steingrímsson et al, 1994;Tachibana et al, 2003). To determine whether specific alterations in melanocyte functions (such as differentiation and proliferation) are caused by MITF mutation, efforts are made to model melanocyte induction in MITF mutant-induced pluripotent stem cells (iPSCs).…”

Hearing Function, Degeneration, and Disease: Spotlight on the Stria Vascularis

“…A de novo mutation in the Mitf promoter isoform, Mitf-M, causes pigmentation loss and hearing damage in mouse and porcine models, indicating that a loss of Mitf-M might hinder melanogenesis in the SV (Chen et al, 2016). Furthermore, RNA sequencing of the SV collected from Mitf-M animals also indicates that ion transport genes such as transmembrane receptor cation channel M1 (Trpm1), Kcnj13, and solute carrier 45A2 (Slc45a2) are downregulated (Chen et al, 2020). These results suggest that melanin-producing cells in the SV likely contribute to the ionic regulation of the cochlear fluid, however, ionic measurements are required to confirm this hypothesis.…”