SMAD4 Defect Causes Auditory Neuropathy Via Specialized Disruption of Cochlear Ribbon Synapses in Mice.
More than 100 genes have been associated with deafness. However, SMAD4 is rarely considered a contributor to deafness in humans, except for its well-defined role in cell differentiation and regeneration. Here, we report that a SMAD4 defect in mice can cause auditory neuropathy, which was defined as a mysterious hearing and speech perception disorder in human for which the genetic background remains unclear. Our study showed that a SMAD4 defect induces failed formation of cochlear ribbon synapse during the earlier stage of auditory development in mice. Further investigation found that there are nearly normal morphology of outer hair cells (OHCs) and post-synapse spiral ganglion nerves (SGNs) in SMAD4 conditional knockout mice (cKO); however, a preserved distortion product of otoacoustic emission (DPOAE) and cochlear microphonic (CM) still can be evoked in cKO mice. Moreover, a partial restoration of hearing detected by electric auditory brainstem response (eABR) has been obtained in the cKO mice using electrode stimuli toward auditory nerves. Additionally, the ribbon synapses in retina are not affected by this SMAD4 defect. Thus, our findings suggest that this SMAD4 defect causes auditory neuropathy via specialized disruption of cochlear ribbon synapses.
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Ke
K
Liu
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Fei
F
Ji
The State Key Laboratory of Proteomics, Genetics Laboratory of Development and Disease, Institute of Biotechnology, AMMS, Beijing, 100071, China.
Guan
G
Yang
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Zhaohui
Z
Hou
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Jianhe
J
Sun
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Xiaoyu
X
Wang
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Weiwei
W
Guo
Department of Communicative Disorders and Sciences, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Wei
W
Sun
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
Weiyan
W
Yang
The State Key Laboratory of Proteomics, Genetics Laboratory of Development and Disease, Institute of Biotechnology, AMMS, Beijing, 100071, China. yangx@bmi.ac.cn.
Xiao
X
Yang
Department of Otolaryngology, Head and Neck Surgery, The Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China. yangsm301@263.net.
Shiming
S
Yang
D000818:Animals; D001489:Basilar Membrane / Q000378:metabolism / Q000473:pathology; D003051:Cochlea / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D003056:Cochlear Nerve / Q000378:metabolism / Q000473:pathology; D004558:Electric Stimulation; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D034381:Hearing Loss / Q000378:metabolism / Q000473:pathology; D006313:Hearing Loss, Central / Q000473:pathology*; D018345:Mice, Knockout; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D014158:Transcription, Genetic; D014785:Vision, Ocular
D051901:Smad4 Protein; C490810:Smad4 protein, mouse
Auditory neuropathy; Cochlea; Deafness; Retina; Ribbon synapse; SMAD4