Development and transdifferentiation into inner hair cells require Tbx2

Zhenghong Bi; Xiang Li; Minhui Ren; Yunpeng Gu; Tong Zhu; Shuting Li; Guangqin Wang; Suhong Sun; Yuwei Sun; Zhiyong Liu

doi:10.1093/nsr/nwac156

Development and transdifferentiation into inner hair cells require Tbx2

Natl Sci Rev. 2022 Aug 9;9(12):nwac156. doi: 10.1093/nsr/nwac156. eCollection 2022 Dec.

Authors

Zhenghong Bi¹, Xiang Li¹, Minhui Ren^{1

2}, Yunpeng Gu^{1

2}, Tong Zhu¹, Shuting Li^{1

2}, Guangqin Wang^{1

2}, Suhong Sun^{1

2}, Yuwei Sun^{1

2}, Zhiyong Liu^{1

2

3}

Affiliations

¹ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China.

Abstract

Atoh1 is essential for the development of both outer hair cells (OHCs) and inner hair cells (IHCs) in the mammalian cochlea. Whereas Ikzf2 is necessary for OHC development, the key gene required for IHC development remains unknown. We found that deletion of Tbx2 in neonatal IHCs led to their transdifferentiation into OHCs by repressing 26.7% of IHC genes and inducing 56.3% of OHC genes, including Ikzf2. More importantly, persistent expression of Tbx2 coupled with transient Atoh1 expression effectively reprogrammed non-sensory supporting cells into new IHCs expressing the functional IHC marker vGlut3. The differentiation status of these new IHCs was considerably more advanced than that previously reported. Thus, Tbx2 is essential for IHC development and co-upregulation of Tbx2 with Atoh1 in supporting cells represents a new approach for treating deafness related to IHC degeneration.

Keywords: Ikzf2; Tbx2; cochlea; inner hair cell; outer hair cell; supporting cell.