RESEARCH ARTICLE Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models Kyeong-Hye Moon1,2, Ji-Hyun Ma1, Hyehyun Min1, Heiyeun Koo1,2, HongKyung Kim1, Hyuk Wan Ko3*, Jinwoong Bok1,2,4* 1Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea; 2BK21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; 4Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea 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. *For correspondence:
[email protected] (HWK);
[email protected] (JB) Competing interests: The Introduction authors declare that no The primary cilium is a microtubule-based organelle protruding from the apical surface of nearly all competing interests exist.