Gαi Proteins are Indispensable for Hearing.
Cell Physiol Biochem. 2018-01-01; 47(4): 1509-1532
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1. Cell Physiol Biochem. 2018;47(4):1509-1532. doi: 10.1159/000490867. Epub 2018 Jun 21.
Beer-Hammer S(1), Lee SC(2), Mauriac SA(3)(4), Leiss V(1), Groh IAM(1), Novakovic A(1), Piekorz RP(5), Bucher K(1), Chen C(2), Ni K(2), Singer W(2), Harasztosi C(6), Schimmang T(7), Zimmermann U(2), Pfeffer K(8), Birnbaumer L(9)(10), Forge A(11), Montcouquiol M(3)(4), Knipper M(2), Nürnberg B(1), Rüttiger L(2).
(1)Department of Pharmacology and Experimental Therapy, and Interfaculty Center
of Pharmacogenomics and Drug Research (ICePhA), University of Tübingen, Tübingen,
(2)Molecular Physiology of Hearing, Tübingen Hearing Research Centre, Department
of Otolaryngology, University of Tübingen, Tübingen, Germany.
(3)INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, Bordeaux, France.
(4)University of Bordeaux, Neurocentre Magendie, Bordeaux, France.
(5)Institute for Biochemistry and Molecular Biology II, Medical Faculty,
University of Düsseldorf, Düsseldorf, Germany.
(6)Department of Otolaryngology, Tübingen Hearing Research Center, Section of
Physiological Acoustics and Communication, University of Tübingen, Tübingen,
(7)Instituto de Biologíay Genética Molecular, Universidad de Valladolid y Consejo
Superior de Investigaciones Científicas, Valladolid, Spain.
(8)Institute of Medical Microbiology and Hospital Hygiene, University of
Düsseldorf, Düsseldorf, Germany.
(9)Neurobiology Laboratory, National Institute of Environmental Health Sciences,
National Institute of Health, Research Triangle Park, North Carolina, USA.
(10)Institute of Biomedical Research (BIOMED), School of Medical Sciences,
Catholic University of Argentina, Buenos Aires, Argentina.
(11)UCL Ear Institute, London, United Kingdom.
BACKGROUND/AIMS: From invertebrates to mammals, Gαi 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
Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 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 Gαi3 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 Gαi 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 Gαi 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 Gαi3 but not of the ubiquitously expressed
Gαi2 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 Gαi2 or Gαi3 had no impact. In contrast,
double-deficiency for Gαi2 and Gαi3 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 Gαi3-deficient mice revealed
that the amplitude of ABR wave IV was disproportionally elevated in comparison to
ABR wave I indicating that Gαi3 is selectively involved in generation of neural
gain during auditory processing.
CONCLUSION: We propose a so far unrecognized complexity of isoform-specific and
overlapping Gαi protein functions particular during final differentiation
© 2018 The Author(s). Published by S. Karger AG, Basel.
PMID: 29940568 [Indexed for MEDLINE]