Down-regulation of msrb3 and destruction of normal auditory system development through hair cell apoptosis in zebrafish.
Hearing defects can significantly influence quality of life for those who experience them. At this time, 177 deafness genes have been cloned, including 134 non-syndromic hearing-loss genes. The methionine sulfoxide reductase B3 (Ahmed et al., 2011) gene (also called DFNB74) is one such newly discovered hearing-loss gene. Within this gene c.265 T>G and c.55 T>C mutations are associated with autosomal recessive hearing loss. However, the biological role and mechanism underlying how it contributes to deafness is unclear. Thus, to better understand this mutation, we designed splicing morpholinos for the purpose of down-regulating msrb3 in zebrafish. Morphants exhibited small, tiny, fused, or misplaced otoliths and abnormal numbers of otoliths. Down-regulation of msrb3 also caused shorter, thinner, and more crowded cilia. Furthermore, L1-8 neuromasts were reduced and disordered in the lateral line system; hair cells in each neuromast underwent apoptosis. Co-injection with human MSRB3 mRNA partially rescued auditory system defects, but mutant MSRB3 mRNA could not. Thus, msrb3 is instrumental for auditory system development in zebrafish and MSRB3-related deafness may be caused by promotion of hair cell apoptosis.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Medical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Xiaofang
X
Shen
Fei
F
Liu
Yingzhi
Y
Wang
Huijun
H
Wang
Jing
J
Ma
Wenjun
W
Xia
Jin
J
Zhang
Nan
N
Jiang
Shaoyang
S
Sun
Xu
X
Wang
Duan
D
Ma
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D015536:Down-Regulation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D005816:Genetic Complementation Test; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D051150:Methionine Sulfoxide Reductases / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins; D051150:Methionine Sulfoxide Reductases; C000609905:methionine sulfoxide reductase B3, zebrafish; C524352:MSRB3 protein, human