GATA3 maintains the quiescent state of cochlear supporting cells by regulating p27kip1

Jiadong Xu,Dongliang Yu,Xiaoling Xie,Xuhui Dong,Luming Guo,Lin Gan,Qi Tang,Mei Xu,Liang Huang

doi:10.1038/s41598-021-95427-3

Abstract

Haplo-insufficiency of the GATA3 gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome. Previous studies have shown that Gata3 is required for the development of the prosensory domain and spiral ganglion neurons (SGNs) of the mouse cochlea during embryogenesis. However, its role in supporting cells (SCs) after cell fate specification is largely unknown. In this study, we used tamoxifen-inducible Sox2CreERT2 mice to delete Gata3 in SCs of the neonatal mouse cochlea and showed that loss of Gata3 resulted in the proliferation of SCs, including the inner pillar cells (IPCs), inner border cells (IBCs), and lateral greater epithelium ridge (GER). In addition, loss of Gata3 resulted in the down-regulation of p27kip1, a cell cycle inhibitor, in the SCs of Gata3-CKO neonatal cochleae. Chromatin immunoprecipitation analysis revealed that GATA3 directly binds to p27kip1 promoter and could maintain the quiescent state of cochlear SCs by regulating p27kip1 expression. Furthermore, RNA-seq analysis revealed that loss of Gata3 function resulted in the change in the expression of genes essential for the development and function of cochlear SCs, including Tectb, Cyp26b1, Slitrk6, Ano1, and Aqp4.

Highlights

Haplo-insufficiency of the GATA-binding protein 3 (GATA3) gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome
Our results revealed that the deletion of Gata[3] in neonatal cochleae led to the downregulation of p 27kip[1] expression and cell cycle re-entry of supporting cells (SCs)
We co-labeled cochleae of wild type mice with antibodies against GATA3 and SOX2, a SC marker, and revealed that GATA3 was broadly expressed in the greater epithelial ridge (GER), inner border cells (IBCs), inner phalangeal cells (IPhCs), inner pillar cells (IPCs), outer pillar cells (OPCs), Deiters’ cells (DCs), Hensen’s cells (HeCs), hair cells (HCs), Claudius’ cells (CCs), and cells in the outer sulcus at postnatal day 0 (P0) and P7 (Fig. 1A–F,A′–F′)

Summary

Introduction

Haplo-insufficiency of the GATA3 gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome. Haplo-insufficiency of the GATA3 gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, known as Barakat syndrome. Among these three phenotypes, all patients have some form of sensorineural deafness and many suffer from congenital d eafness[10,11], suggesting GATA3’s essential role in cochlear development. Our results revealed that the deletion of Gata[3] in neonatal cochleae led to the downregulation of p 27kip[1] expression and cell cycle re-entry of SCs. chromatin immunoprecipitation (ChIP) analysis showed that GATA3 directly binds to the promoter of p27kip[1]. Our data demonstrated that GATA3 maintains the quiescent state of SCs by regulating the expression of p27Kip[1]

Methods

Results

Conclusion