title: All Akt isoforms (Akt1, Akt2, Akt3) are involved in normal hearing, but only Akt2 and Akt3 are involved in auditory hair cell survival in the mammalian inner ear.
abstract: The kinase Akt is a key downstream mediator of the phosphoinositide-3-kinase signaling pathway and participates in a variety of cellular processes. Akt comprises three isoforms each encoded by a separate gene. There is evidence to indicate that Akt is involved in the survival and protection of auditory hair cells in vitro. However, little is known about the physiological role of Akt in the inner ear-especially in the intact animal. To elucidate this issue, we first analyzed the mRNA expression of the three Akt isoforms in the inner ear of C57/BL6 mice by real-time PCR. Next, we tested the susceptibility to gentamicin-induced auditory hair cell loss in isoform-specific Akt knockout mice compared to wild-types (C57/BL6) in vitro. To analyze the effect of gene deletion in vivo, hearing and cochlear microanatomy were evaluated in Akt isoform knockout animals. In this study, we found that all three Akt isoforms are expressed in the cochlea. Our results further indicate that Akt2 and Akt3 enhance hair cell resistance to ototoxicity, while Akt1 does not. Finally, we determined that untreated Akt1 and Akt2/Akt3 double knockout mice display significant hearing loss, indicating a role for these isoforms in normal hearing. Taken together, our results indicate that each of the Akt isoforms plays a distinct role in the mammalian inner ear.
authors: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors: Yves
authors: Y
authors: Brand
authors: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors: Soledad
authors: S
authors: Levano
authors: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors: Vesna
authors: V
authors: Radojevic
authors: Inner Ear Research, Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Zürich, Frauenklinikstrasse 24, NORD 2, 8091 Zürich, Switzerland.
authors: Arianne Monge
authors: AM
authors: Naldi
authors: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors: Cristian
authors: C
authors: Setz
authors: Departments of Surgery/Otolaryngology, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093, United States of America; Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093, United States of America; San Diego VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, United States of America.
authors: Allen F
authors: AF
authors: Ryan
authors: Departments of Surgery/Otolaryngology, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093, United States of America; San Diego VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, United States of America.
authors: Kwang
authors: K
authors: Pak
authors: Mechanisms of Cancer Program, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Brian A
authors: BA
authors: Hemmings
authors: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors: Daniel
authors: D
authors: Bodmer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D004198:Disease Susceptibility; D016057:Evoked Potentials, Auditory, Brain Stem; D015971:Gene Expression Regulation, Enzymologic; D005839:Gentamicins; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000201:enzymology*; D006309:Hearing / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D008322:Mammals / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013136:Spiral Ganglion / Q000201:enzymology; D013316:Stria Vascularis / Q000201:enzymology
chemical_list: D005839:Gentamicins; D007527:Isoenzymes; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt