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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2019, Vol. 13 Issue (6) : 690-704    https://doi.org/10.1007/s11684-018-0638-8
RESEARCH ARTICLE
Tprn is essential for the integrity of stereociliary rootlet in cochlear hair cells in mice
Yuqin Men1, Xiujuan Li2, Hailong Tu1, Aizhen Zhang1, Xiaolong Fu1, Zhishuo Wang1, Yecheng Jin1, Congzhe Hou3, Tingting Zhang1, Sen Zhang1, Yichen Zhou1, Boqin Li4,5, Jianfeng Li6, Xiaoyang Sun1(), Haibo Wang6(), Jiangang Gao1()
1. School of Life Science, Shandong University, Jinan 250100, China
2. Rizhao Polytechnic, Rizhao 276826, China
3. The Second Hospital of Shandong University, Jinan 250033, China
4. Electron Microscopy Laboratory, Shandong Institute of Otolaryngology, Jinan 250022, China
5. Laboratory of Electron Microscopy, Jinan WEI-YA Biotech Company, Jinan 250100, China
6. Department of Otolaryngology-Head and Neck Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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Abstract

Tprn encodes the taperin protein, which is concentrated in the tapered region of hair cell stereocilia in the inner ear. In humans, TPRN mutations cause autosomal recessive nonsyndromic deafness (DFNB79) by an unknown mechanism. To determine the role of Tprn in hearing, we generated Tprn-null mice by clustered regularly interspaced short palindromic repeat/Cas9 genome-editing technology from a CBA/CaJ background. We observed significant hearing loss and progressive degeneration of stereocilia in the outer hair cells of Tprn-null mice starting from postnatal day 30. Transmission electron microscopy images of stereociliary bundles in the mutant mice showed some stereociliary rootlets with curved shafts. The central cores of the stereociliary rootlets possessed hollow structures with surrounding loose peripheral dense rings. Radixin, a protein expressed at stereocilia tapering, was abnormally dispersed along the stereocilia shafts in Tprn-null mice. The expression levels of radixin and β-actin significantly decreased. We propose that Tprn is critical to the retention of the integrity of the stereociliary rootlet. Loss of Tprn in Tprn-null mice caused the disruption of the stereociliary rootlet, which resulted in damage to stereociliary bundles and hearing impairments. The generated Tprn-null mice are ideal models of human hereditary deafness DFNB79.
Keywords TPRN      stereocilia      stereociliary rootlet      actin filament      CRISPR/Cas9      hearing     
Corresponding Author(s): Xiaoyang Sun,Haibo Wang,Jiangang Gao   
Just Accepted Date: 10 May 2018   Online First Date: 31 August 2018    Issue Date: 16 December 2019
 Cite this article:   
Yuqin Men,Xiujuan Li,Hailong Tu, et al. Tprn is essential for the integrity of stereociliary rootlet in cochlear hair cells in mice[J]. Front. Med., 2019, 13(6): 690-704.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0638-8
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I6/690
Fig.1  CRISPR/Cas9-mediated generation of Tprn-null mice. (A) Diagram of stereociliary bundles in cochlear hair cells. The core of the stereocilia is composed of actin filaments. A tapered structure is located in the basal region of the stereocilia near the insertion site on the apical surface of the hair cell. (B) Schematic of the strategy. The target site (blue arrowhead) is located in exon 1 after the initiation codon ATG (green arrow). Red represents the protospacer adjacent motif (PAM) sequence. (C) DNA sequencing of the PCR products from WT and TPRN mutant mice at F0. The sequencing chromatograms show two mutation types. The red boxed area represents the initiation codon ATG. Red arrows signify the start sites of the mutations in mutants 1 and 2. (D) Sequences of the two mutation types (43- and 1-bp deletions). Both mutations can cause a frameshift in the TPRN gene. (E) Mouse genotyping by PCR analysis of Tprn-null mice (43-bp deletion). Lanes: heterozygous (+/-), WT (+/+), and homozygous mice (-/-). The PCR products of the WT allele was 443 bp long, the PCR products of the heterozygous TPRN null alleles were 400 and 443 bp long, and the PCR product of the homozygous TPRN null allele was 400 bp long.
Fig.2  Expression pattern of TPRN in cochlear hair cells of WT mice. (A) Gross morphology of P21 WT and Tprn-null mice. No obvious difference, including that in the body size, was noted. Scale bar: 1 cm. (B) Confocal images of cochlear hair cells stained with anti-taperin antibody in P30 WT and Tprn-null mice. TPRN was enriched at the basal tapered region of stereociliary bundles in cochlear hair cells (arrows) in the WT mice. Taperin expression was not detected in the cochlear hair cells of Tprn-null mice. The inserts represent high-magnification views of the boxed areas. Red, phalloidin; green, TPRN. Scale bar: 20 mm.
Fig.3  ABR test in WT and Tprn-null mice at different ages. (A) ABR measurements for broadband click in the 1, 2, 4, and 6 month-old mice. (B–E) ABR measurements for frequency-specific pure tone stimulation in the 1, 2, 4, and 6 month-old mice. (F) Hearing thresholds by ABR testing for frequency-specific pure tone stimulation in Tprn-null mice at 1 and 6 months of age. The data indicated a progressive elevation of thresholds from 1 month to 6 months of age. * P<0.05; ** P<0.01; *** P<0.001 compared with the WT thresholds at the corresponding frequency as determined by Student’s t-test; n>4.
Fig.4  Immunostaining of whole-mount cochleae from WT and Tprn-null mice. (A) Confocal images of hair cells stained with the F-actin dye phalloidin, the hair cell marker myosin VIIa (red), the OHC lateral membrane marker prestin (green), and the cell-nucleus-specific dye DAPI (blue) in 1 month-old mice. No obvious defect was found in the hair cells of the Tprn-null mice. Scale bars: 20 mm. (B) Confocal images of hair cells stained with phalloidin, myosin VIIa (red), prestin (green), and DAPI (blue) in 4 month-old mice. The morphology of the hair cells appears normal. Scale bars: 20 mm. (C) High-magnification images of stereociliary bundles show evident gaps in the stereociliary bundle and indicate a loss of stereocilia in the 4 month-old Tprn-null mice (arrowheads). Scale bars: 20 mm. (D) Confocal images of hair cells stained with myosin VIIa (green) in 6 month-old mice. A severe hair cell loss was observed in the basal turn of cochlea in TPRN-null mice. Scale bars: 50 mm.
Fig.5  SEM images of stereocilia in Tprn-null mice. (A) Images of hair cell bundles in the WT and Tprn-null mice at 1 month of age. (B) Images of hair cell bundles in the WT and Tprn-null mice at 2 months of age. (C) Images of hair cell bundles in the WT and Tprn-null mice at 4 months of age. Scale bars: 10 mm for HCs; 2 mm for OHCs; 5 mm for IHCs.
Fig.6  Defects in the tapered region of stereocilia and some elongated stereocilia in Tprn-null mice. (A) SEM images of stereocilia in mice at P12, P14, P30, P60, and P120. The diameters of the tapered region in the stereocilia were thinner in the Tprn-null mice than in the WT mice, starting from 1 month of age. Red inserts represent a high-magnification view of the red boxed areas. Highly magnified images of stereociliary bundles show evident gaps in the stereocilia of Tprn-null mice at P120. Scale bar: 5 mm. (A?) Statistical analysis of the diameters of the tapered region in the innermost row of stereocilia. OHCs were selected in the same region at the midbasal turn of the cochlea, and the diameters of the tapered region in the stereocilia were measured. Data are shown as the mean±standard error around the mean. Significance was calculated by Student’s t-test. *P<0.05; ** P<0.01; *** P<0.001; n>10. (B) SEM images of stereocilia at the apical turn of the cochlear OHCs at the ages of 1, 2, and 4 months.
Fig.7  Disrupted structure of stereociliary rootlets in TPRN-null mice. (A) TEM images of the vertical ultrathin sections of hair cells at the middle–basal turns of the cochlea in the 2 month-old mice. In the WT mice, the stereociliary rootlets of the stereocilia were straight (white arrowheads) and penetrating into the cuticular plate. By contrast, the stereociliary rootlets curved (black arrowheads) in the Tprn-null mice. Scale bars: 500 nm. (B) TEM images of the horizontal sections of stereociliary bundles in the 2 month-old mice. In the WT hair cells, an electron-dense central core and a peripheral-dense ring around the stereociliary rootlets were observed at the stereocilium base (white arrowheads). In the Tprn-null mice, a loose peripheral ring was observed surrounding the core actin structure (white arrowheads) but not in the WT mice. Scale bars: 500 nm. (C) High-magnification view of the red boxed areas in Fig.7B. In the WT hair cells, horizontal sections showed a uniformly aligned electron-dense central core (yellow arrowheads) (black arrows) on the apical surface of cochlear hair cells. In the Tprn-null mice, the core of stereociliary rootlets shows an evident hollow structure (yellow arrowheads). The stereociliary rootlets in the three rows were arranged disorderly (black arrows). Scale bar: 200 nm.
Fig.8  Analysis of mechanotransduction channels in the hair cells of Tprn-null mice. FM1-43 uptake assay in the hair cells of WT and Tprn-null mice at 4 months of age. The FM1-43 assay in the WT mice displayed high FM1-43 uptake, whereas the TPRN-null hair cells exhibited very low FM1-43 uptake.
Fig.9  Ectopic localization of radixin and decreased levels of radixin and b-actin in TPRN-null cochleae. (A, B) Radixin protein localization in the hair cells of 2 month-old mice. (A) In the WT mice, radixin staining was mainly detected at the base of the stereociliary bundles. (B) In the Tprn-null mice, radixin was diffusely distributed along the stereocilia shafts. (a1, a2; b1, b2) Boxed areas represent the high-magnification view in the WT mice (a1, a2) and Tprn-null mice (b1, b2). Red, phalloidin; green, radixin. Scale bars: 20 mm. (C, D) Western blot analysis of radixin (C) and b-actin (D) protein levels in the mouse cochleae at P30. (C) Radixin protein quantification indicated that the expression levels were significantly decreased in the Tprn-null mice. (D) b-actin protein quantification denoted that the expression levels were significantly decreased in the Tprn-null mice. The data were normalized against the results of the WT mice. Error bars indicate the standard error around the mean. * P<0.05; ** P<0.01; *** P<0.001 compared with the WT mice by Student’s t-test; n=3. (E) Model of actin filament core and actin-binding proteins, including taperin, at the tapered region of stereocilia. Fam65b formed a circumferential ring-like structure at the tapered region of stereocilia. TPRN was inside the ring-like structure and formed a protein complex with Clic5 and radixin. The TPRN-related protein complex could stabilize membrane/actin filament linkages in the cochlear stereocilia, including stereociliary rootlets. The dense structure of actin filaments in a stereociliary rootlet was critical for maintaining and stabilizing stereocilia.
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