LKB1 Is Required for the Development and Maintenance of Stereocilia in Inner Ear Hair Cells in Mice.
The LKB1 gene, which encodes a serine/threonine kinase, was discovered to play crucial roles in cell differentiation, proliferation, and the establishment of cell polarity. In our study, LKB1 conditional knockout mice (Atoh1-LKB1-/- mice) were generated to investigate LKB1 function in the inner ear. Tests of auditory brainstem response and distortion product otoacoustic emissions revealed significant decreases in the hearing sensitivities of the Atoh1-LKB1-/- mice. In Atoh1-LKB1-/- mice, malformations of hair cell stereocilliary bundles were present as early as postnatal day 1 (P1), a time long before the maturation of the hair cell bundles. In addition, we also observed outer hair cell (OHC) loss starting at P14. The impaired stereocilliary bundles occurred long before the presence of hair cell loss. Stereociliary cytoskeletal structure depends on the core actin-based cytoskeleton and several actin-binding proteins. By Western blot, we examined actin-binding proteins, specifically ERM (ezrin/radixin/moesin) proteins involved in the regulation of the actin cytoskeleton of hair cell stereocilia. Our results revealed that the phosphorylation of ERM proteins (pERM) was significantly decreased in mutant mice. Thus, we propose that the decreased pERM may be a key factor for the impaired stereocillia function, and the damaged stereocillia may induce hair cell loss and hearing impairments. Taken together, our data indicates that LKB1 is required for the development and maintenance of stereocilia in the inner ear.
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Yuqin
Y
Men
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Aizhen
A
Zhang
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Haixiang
H
Li
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Tingting
T
Zhang
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Yecheng
Y
Jin
SARITEX Center for Stem Cell, Engineering Translational Medicine, Shanghai East Hospital, Advanced Institute of Translational Medicine, Tongji University School of Medicine, Shanghai, China; Center for Stem Cell&Nano-Medicine, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China; Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
Huashun
H
Li
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Jian
J
Zhang
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China.
Jiangang
J
Gao
D055372:AMP-Activated Protein Kinases; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059547:Stereocilia / Q000378:metabolism*; D000099149:Ezrin
D055372:AMP-Activated Protein Kinases; D051792:Basic Helix-Loop-Helix Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000099149:Ezrin; C500943:Atoh1 protein, mouse; C071058:moesin; C071776:radixin; C491654:Stk11 protein, mouse