Gαi Proteins are Indispensable for Hearing

Background/Aims: From invertebrates to mammals, Gα i proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gα i3 -deficiency in pre-hearing murine cochleae pointed to a role of...

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Published in:	Cellular physiology and biochemistry Vol. 47; no. 4; pp. 1509 - 1532
Main Authors:	Beer-Hammer, Sandra, Lee, Sze Chim, Mauriac, Stephanie A., Leiss, Veronika, Groh, Isabel A. M., Novakovic, Ana, Piekorz, Roland P., Bucher, Kirsten, Chen, Chengfang, Ni, Kun, Singer, Wibke, Harasztosi, Csaba, Schimmang, Thomas, Zimmermann, Ulrike, Pfeffer, Klaus, Birnbaumer, Lutz, Forge, Andrew, Montcouquiol, Mireille, Knipper, Marlies, Nürnberg, Bernd, Rüttiger, Lukas
Format:	Journal Article
Language:	English
Published:	Basel, Switzerland S. Karger AG 2018 Cell Physiol Biochem Press GmbH & Co KG
Subjects:	Animals Carrier Proteins - genetics Carrier Proteins - metabolism Cell division Cloning Cochlear hair cell maturation Deafness gene Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism GTP-Binding Protein alpha Subunit, Gi2 - genetics GTP-Binding Protein alpha Subunit, Gi2 - metabolism GTP-Binding Protein alpha Subunits, Gi-Go - genetics GTP-Binding Protein alpha Subunits, Gi-Go - metabolism Gαi3/GNAI3 Hair Cells, Auditory, Inner - cytology Hair Cells, Auditory, Inner - metabolism Hearing - physiology Hearing loss Heterotrimeric G-proteins Mice Mice, Transgenic Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neural gain Neurosciences Original Paper Physiology Proteins Stereocilia bundle Thyroid gland United States > US Heterotrimeric G-proteins Stereocilia bundle Deafness gene Cochlear hair cell maturation Gαi3/GNAI3 Neural gain
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Summary:	Background/Aims: From invertebrates to mammals, Gα i proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gα i3 -deficiency in pre-hearing murine cochleae pointed to a role of Gα i3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary (“hair”) bundle, a requirement for the progression of mature hearing. We found that the lack of Gα i3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Methods: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gα i proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gα i isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. Results: Here we report that lack of Gα i3 but not of the ubiquitously expressed Gα i2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gα i2 or Gα i3 had no impact. In contrast, double-deficiency for Gα i2 and Gα i3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gα i3 -deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gα i3 is selectively involved in generation of neural gain during auditory processing. Conclusion: We propose a so far unrecognized complexity of isoform-specific and overlapping Gα i protein functions particular during final differentiation processes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1015-8987 1421-9778
DOI:	10.1159/000490867