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

Rohacek, Alex M; Bebee, Thomas W.; Tilton, Richard K.; Radens, Caleb M.; McDermott-Roe, Chris; Peart, Natoya; Kaur, Maninder; Zaykaner, Michael; Cieply, Benjamin; Musunuru, Kiran; Barash, Yoseph; Germiller, John A.; Krantz, Ian D.; Carstens, Russ P.; Epstein, Douglas J.

doi:10.1016/j.devcel.2017.09.026

Cited by 47 publications

(46 citation statements)

References 80 publications

(98 reference statements)

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“…However, deletion of exon IIIb in the mice did not default to splicing of exon IIIc in epithelial cells, but instead caused skipping of both exons and a frameshift that effectively resulted in no Fgfr2 expression in epithelial cells (De Moerlooze et al, 2000). In contrast, ablation of Esrp1 induces a switch in isoforms, such that ectopic Fgfr2-IIIc in epithelial cells can still respond to Fgf ligands to sustain Fgf signaling as we demonstrated in a prior study (Rohacek et al, 2017). These observations strongly suggest that altered splicing of Fgfr2 does not account for the cleft lip observed in Esrp1 −/− mice and is also unlikely to underlie the cleft palate.…”

Section: Discussionsupporting

confidence: 59%

Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Zhang

et al. 2019

Preprint

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Running Title: Altered Wnt signaling and CL/P in Esrp1 KO mice (32 characters) SUMMARY STATEMENT 3Ablation of the epithelial-specific splicing factor Esrp1 leads to cleft lip and cleft palate (CL/P) and this 4 study identifies alterations in Wnt signaling during face formation that may partly underlie this defect. 5 6 7 ABSTRACT 8 9Cleft lip is one of the most highly prevalent birth defects in human patients. However, there remain a 10 limited number of mouse models of cleft lip and thus much work is needed to further characterize genes 11 and mechanisms that lead to this disorder. It is well established that crosstalk between epithelial and 12 mesenchymal cells underlies formation of the face and palate, yet the basic molecular events mediating 13 this crosstalk are still poorly understood. We previously demonstrated that mice with ablation of the 14 epithelial-specific splicing factor Esrp1 have fully penetrant bilateral CL/P. In this study we further 15 investigated the mechanisms by which ablation of Esrp1 leads to cleft lip as well as cleft palate. These 16 studies included a detailed analysis of the changes in splicing and total gene expression in embryonic 17 ectoderm during formation of the face as well as gene expression changes in adjacent mesenchyme. We 18 identified altered expression in components of pathways previously implicated in cleft lip and/or palate, 19 including numerous components of the Wnt signaling pathway. These findings illustrate that maintenance 20 of an Esrp1 regulated epithelial splicing program is essential for face development through regulation of 21 key signaling pathways. 22 23 24 25 26 27 28 29Cleft lip and/or palate (CL/P) are among the most common congenital birth defects, affecting 30 approximately 1 in 700 live births and affected children face a variety of health and psychosocial 31 problems as well as a need for extensive surgical and dental treatments (Dixon et al., 2011). The causes of 32 CL/P are heterogeneous and include a variety of environmental and genetic factors. Although CL/P can 33 be a component of disease syndromes, most cases of CL/P are non-syndromic. Cleft lip with or without 34 cleft palate (CL/P) is more common in human patients than isolated cleft palate (CP, or CPO) and these 35 disorders are largely genetically and etiologically distinct (Fraser, 1970; Gritli-Linde, 2008).The proper 36 development of the lip and palate is similar between humans and mice and thus mouse models have 37 served an important role in studies to identify genes and characterize pathways that, when disrupted, lead 38 to CL/P or CPO (Gritli-Linde, 2012; Juriloff and Harris, 2008). In mice, formation of the face commences 39 around E9.5 and involves the five facial prominences consisting of mostly neural crest-derived 40 mesenchyme and overlying epithelium; the frontonasal prominence (FNP) and the paired maxillary and 41 mandibular prominences (MXP and MdP) (Jiang et al., 2006). The FNP gives rise to the lateral and 42 medial nasal prominences (LNP and MNP) and these prominence...

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Section: Discussionsupporting

confidence: 59%

Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Zhang

et al. 2019

Preprint

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“…Here, we will focus the analyses on the marginal, intermediate, basal, and spindle/root cell clusters. Feature plots of both scRNA-Seq and snRNA-Seq datasets demonstrate the correlation of known gene expression for marginal cells (Kcne1, Kcnq1) (Wangemann, 2002), intermediate cells (Cd44, Met) (Shibata et al, 2016;Rohacek et al, 2017), basal cells (Cldn11, Tjp1) (Gow, 2004;Lee et al, 2017;Liu et al, 2017), and spindle/root cells (Slc26a4) between the two datasets ( Figures 2B,D) (Nishio et al, 2016). Violin plots demonstrate relative expression of these known SV cell type-specific genes across the four main cell types (Figures 2C,E).…”

Section: Stria Vascularis (Sv) Cell Types Exhibit Clear Transcriptionmentioning

confidence: 99%

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

Korrapati

Taukulis

Olszewski

et al. 2019

Front. Mol. Neurosci.

128

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The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

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“…Similarly, disrupting the splicing factor Sfswap in mice, causes vestibular and cochlear defects most likely through gene disruption of the Notch signaling pathway (Moayedi et al, 2014 ). More recently, mutations in epithelial splicing-regulatory protein ESRP1 have been linked to deafness in humans and inner ear developmental defects in mice (Rohacek et al, 2017 ), as a consequence of more than 500 mis-splicing events.…”

Section: Splicing Governing Expression and Functionmentioning

confidence: 99%

Intracellular Regulome Variability Along the Organ of Corti: Evidence, Approaches, Challenges, and Perspective

et al. 2018

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The mammalian hearing organ is a regular array of two types of hair cells (HCs) surrounded by six types of supporting cells. Along the tonotopic axis, this conserved radial array of cell types shows longitudinal variations to enhance the tuning properties of basilar membrane. We present the current evidence supporting the hypothesis that quantitative local variations in gene expression profiles are responsible for local cell responses to global gene manipulations. With the advent of next generation sequencing and the unprecedented array of technologies offering high throughput analyses at the single cell level, transcriptomics will become a common tool to enhance our understanding of the inner ear. We provide an overview of the approaches and landmark studies undertaken to date to analyze single cell variations in the organ of Corti and discuss the current limitations. We next provide an overview of the complexity of known regulatory mechanisms in the inner ear. These mechanisms are tightly regulated temporally and spatially at the transcription, RNA-splicing, mRNA-regulation, and translation levels. Understanding the intricacies of regulatory mechanisms at play in the inner ear will require the use of complementary approaches, and most probably, a combinatorial strategy coupling transcriptomics, proteomics, and epigenomics technologies. We highlight how these data, in conjunction with recent insights into molecular cell transformation, can advance attempts to restore lost hair cells.

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

Cited by 47 publications

References 80 publications

Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Cleft lip and cleft palate (CL/P) inEsrp1KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

Intracellular Regulome Variability Along the Organ of Corti: Evidence, Approaches, Challenges, and Perspective

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