期刊
G3-GENES GENOMES GENETICS
卷 8, 期 10, 页码 3221-3230出版社
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.118.200405
关键词
Fascin2; mutation; TALEN; hearing loss; hair cell; retinitis pigmentosa
资金
- National Natural Science Foundation of China - Shandong Scientific and Technological Development Foundation [81771020, 81570927, 81271092, 2014GSF118083]
- Shandong Scientific and Technological Development Foundation for Healthcare [2015WS0507]
- Research Initiation Grant of Binzhou Medical University [BY2012KYQD01]
- [tshw20110515]
Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 (FSCN2) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice. To explore the function of the gene, Fscn2 was knocked out using TALEN (transcription activator-like effector nucleases) on the C57BL/6J background. Four mouse strains with deletions of 1, 4, 5, and 41 nucleotides in the target region of Fscn2 were developed. F1 heterozygous (Fscn2(+/-)) mice carrying the same deletion of 41 nucleotides were mated to generate the Fscn2(-/-) mice. As a result, the Fscn2(-/-) mice showed progressive hearing loss, as measured in the elevation of auditory brainstem-response thresholds. The hearing impairment began at age 3 weeks at high-stimulus frequencies and became most severe at age 24 weeks. Moreover, degeneration of hair cells and loss of stereocilia were remarkable in Fscn2(-/-) mice, as revealed by F-actin staining and scanning electron microscopy. Furthermore, compared to the controls, the Fscn2(-/-) mice displayed significantly lower electroretinogram amplitudes and thinner retinas at 8, 16, and 24 weeks. These results demonstrate that, in C57BL/6Jmice, Fscn2 is essential for maintaining ear and eye function and that a null mutation of Fscn2 leads to progressive hearing loss and retinal degeneration.
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