Targeted Deletion of All Known Thyroid Hormone Receptors Causes Maturation Retardation and Early-onset Degeneration of Cochlear Outer Sulcus

Thyroid hormone (TH) and/or its receptors (TRs) are essential for hearing, cochlear late-stage development and maintaining endocochlear potential (EP). The mechanism underlying the EP reduction upon deficiency of TH or TRs remains unknown. The cochlear outer sulcus (root cell) is considered to be important for the maintenance of endolymph homeostasis and EP, and undergoes dramatic morphological changes during cochlear late-stage developmental window. It has been long neglected whether TH and/or TRs are required for root cell differentiation and function. Here we demonstrate a key role for TH or TRs in postnatal root cell development and survival in mice. Anti-thyroid drug-induced developmental hypothyroidism results in severe retardation in root cell differentiation. Targeted deletion of both TRα and TRβ but not individual TRβ in cochlear epithelium causes a similar impairment, compounded with an early-onset degeneration of root cells and a reduced EP, without obvious alterations in stria vascularis. Furthermore, we demonstrate that TH signaling acts in parallel with ZBTB20 in the outer sulcus, a transcription factor which we have recently reported to be essential for the outer sulcus differentiation. Our results support that TRα and TRβ act redundantly in promoting root cell late-stage differentiation and maintaining its cellular homeostasis, and root cell dysfunction at least partially contribute to a reduced EP upon deficiency of TH or TRs. These findings imply that root cells may play an important role in maintaining the health of cochlear sensory epithelium and normal EP. Significance Statement Thyroid hormone (TH) and/or its receptors (TRs) are essential for hearing and cochlear development. The cochlear outer sulcus (root cell) is considered to be important for cochlear ionic and metabolic homeostasis. We found that combined deletion of both TRα and TRβ but not individual TRβ results in severe retardation in root cell differentiation accompanied by an early-onset degeneration and a reduced endocochlear potential (EP), suggesting TRα and TRβ act redundantly in promoting root cell differentiation and maintaining its cellular homeostasis. Our findings suggest that root cell dysfunction may at least partially contribute to a reduced EP upon deficiency of TRs, and root cells may play an important role in maintaining the health of cochlear sensory epithelium and EP. ### Competing Interest Statement The authors have declared no competing interest.