Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models

Abstract

Defective primary cilia cause a range of diseases known as ciliopathies, including hearing loss. The etiology of hearing loss in ciliopathies, however, remains unclear. We analyzed cochleae from three ciliopathy mouse models exhibiting different ciliogenesis defects: Intraflagellar transport 88 (Ift88), Tbc1d32 (a.k.a. bromi), and Cilk1 (a.k.a. Ick) mutants. These mutants showed multiple developmental defects including shortened cochlear duct and abnormal apical patterning of the organ of Corti. Although ciliogenic defects in cochlear hair cells such as misalignment of the kinocilium are often associated with the planar cell polarity pathway, our results showed that inner ear defects in these mutants are primarily due to loss of sonic hedgehog signaling. Furthermore, an inner ear-specific deletion of Cilk1 elicits low-frequency hearing loss attributable to cellular changes in apical cochlear identity that is dedicated to low-frequency sound detection. This type of hearing loss may account for hearing deficits in some patients with ciliopathies.

Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling

“…Indeed, we found that defective GLI activator/repressor functions (GLI1 and GLI3) could help to explain the abnormal cochlear development in Osbpl2 –/– mice. Our findings were consistent with a previous report that defective GLI activator/repressor functions, short cochlea, and extra rows of HCs were found in the distal region of the cochlea when Shh signaling transduction was impaired ( 12 ). In addition, we found that OSBPL2 was essential to SMO accumulation in cilia after activation of the Shh signaling pathway.…”

“…Auditory hair cells (HCs) are mechanoreceptors of the auditory system and each HC has an apically located hair bundle made up of a single kinocilium and many stereocilia ( 11 ). Hearing loss (HL) in relation to HCs’ ciliary defects is also considered to be a kind of ciliopathy ( 12 ). To date, studies on cilia-related HL have mainly been focused on stereocilia, which are the key organelles responsible for the conversion of mechanical energy into electrical signals ( 13 – 15 ).…”

“…Webb et al reported that the loss of kinociliary links was considered a cause of abnormal polarity of hair bundles in PCDH15-CD2-deficient mice ( 18 ). Another study found that genetic defects were implicated in differential defective kinocilia including absence of cilia ( Ift88 mutants), morphologically defective cilia ( Tbc1d32 bromi mutants), or abnormally elongated cilia ( Cilk1 mutants), which resulted in HL in mice ( 12 ). However, the molecular mechanism and the key regulators involved in kinociliary development and dynamics have not been thoroughly elucidated.…”

Position Specific Alternative Splicing and Gene Expression Profiles Along the Tonotopic Axis of Chick Cochlea

“…Interestingly, some of the tonotopic features are conserved between the chicken and mouse. For example, the length of the hair bundle, which are composed of tens of stereocilium arranged in a stair-case pattern, is shorter at the base and gradually longer toward the apex, whereas the width of hair bundle is wider at the base and gradually narrower toward the apex ( Son et al, 2015 ; Moon et al, 2020 ).…”

The Kinocilia of Cochlear Hair Cells: Structures, Functions, and Diseases

“…Mutations in some ciliary genes encoding important intraflagellar transport (IFT) proteins such as Ift88 can also cause hearing defects. Ift88 conditional knockout mice exhibit shortened cochlear ducts with multiple extra rows of HCs at the apex, severe hair bundle polarity defects, and premature differentiation of HCs ( Moon et al, 2020 ). Other studies have shown that the phenotypes of these knockout mice all include kinocilium loss, disorderly arrangement of stereocilia of different lengths, short and collapsed structural defects, and mislocation of centrosomes ( Tarchini and Lu, 2019 ).…”