Gαi Proteins are Indispensable for Hearing
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 Gα...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Cell Physiol Biochem Press GmbH & Co KG
2018-06-01
|
| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | https://www.karger.com/Article/FullText/490867 |
| _version_ | 1818888733730013184 |
|---|---|
| author | Sandra Beer-Hammer Sze Chim Lee Stephanie A. Mauriac Veronika Leiss Isabel A. M. Groh Ana Novakovic Roland P. Piekorz Kirsten Bucher Chengfang Chen Kun Ni Wibke Singer Csaba Harasztosi Thomas Schimmang Ulrike Zimmermann Klaus Pfeffer Lutz Birnbaumer Andrew Forge Mireille Montcouquiol Marlies Knipper Bernd Nürnberg Lukas Rüttiger |
| author_facet | Sandra Beer-Hammer Sze Chim Lee Stephanie A. Mauriac Veronika Leiss Isabel A. M. Groh Ana Novakovic Roland P. Piekorz Kirsten Bucher Chengfang Chen Kun Ni Wibke Singer Csaba Harasztosi Thomas Schimmang Ulrike Zimmermann Klaus Pfeffer Lutz Birnbaumer Andrew Forge Mireille Montcouquiol Marlies Knipper Bernd Nürnberg Lukas Rüttiger |
| author_sort | Sandra Beer-Hammer |
| collection | DOAJ |
| description | 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 processes. |
| first_indexed | 2024-12-19T16:57:49Z |
| format | Article |
| id | doaj.art-203fa545a978464bb8f4c71da5a88657 |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-19T16:57:49Z |
| publishDate | 2018-06-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-203fa545a978464bb8f4c71da5a886572022-12-21T20:13:21ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-06-014741509153210.1159/000490867490867Gαi Proteins are Indispensable for HearingSandra Beer-HammerSze Chim LeeStephanie A. MauriacVeronika LeissIsabel A. M. GrohAna NovakovicRoland P. PiekorzKirsten BucherChengfang ChenKun NiWibke SingerCsaba HarasztosiThomas SchimmangUlrike ZimmermannKlaus PfefferLutz BirnbaumerAndrew ForgeMireille MontcouquiolMarlies KnipperBernd NürnbergLukas RüttigerBackground/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 processes.https://www.karger.com/Article/FullText/490867Heterotrimeric G-proteinsGαi3/GNAI3Stereocilia bundleCochlear hair cell maturationNeural gainDeafness gene |
| spellingShingle | Sandra Beer-Hammer Sze Chim Lee Stephanie A. Mauriac Veronika Leiss Isabel A. M. Groh Ana Novakovic Roland P. Piekorz Kirsten Bucher Chengfang Chen Kun Ni Wibke Singer Csaba Harasztosi Thomas Schimmang Ulrike Zimmermann Klaus Pfeffer Lutz Birnbaumer Andrew Forge Mireille Montcouquiol Marlies Knipper Bernd Nürnberg Lukas Rüttiger Gαi Proteins are Indispensable for Hearing Cellular Physiology and Biochemistry Heterotrimeric G-proteins Gαi3/GNAI3 Stereocilia bundle Cochlear hair cell maturation Neural gain Deafness gene |
| title | Gαi Proteins are Indispensable for Hearing |
| title_full | Gαi Proteins are Indispensable for Hearing |
| title_fullStr | Gαi Proteins are Indispensable for Hearing |
| title_full_unstemmed | Gαi Proteins are Indispensable for Hearing |
| title_short | Gαi Proteins are Indispensable for Hearing |
| title_sort | gαi proteins are indispensable for hearing |
| topic | Heterotrimeric G-proteins Gαi3/GNAI3 Stereocilia bundle Cochlear hair cell maturation Neural gain Deafness gene |
| url | https://www.karger.com/Article/FullText/490867 |
| work_keys_str_mv | AT sandrabeerhammer gaiproteinsareindispensableforhearing AT szechimlee gaiproteinsareindispensableforhearing AT stephanieamauriac gaiproteinsareindispensableforhearing AT veronikaleiss gaiproteinsareindispensableforhearing AT isabelamgroh gaiproteinsareindispensableforhearing AT ananovakovic gaiproteinsareindispensableforhearing AT rolandppiekorz gaiproteinsareindispensableforhearing AT kirstenbucher gaiproteinsareindispensableforhearing AT chengfangchen gaiproteinsareindispensableforhearing AT kunni gaiproteinsareindispensableforhearing AT wibkesinger gaiproteinsareindispensableforhearing AT csabaharasztosi gaiproteinsareindispensableforhearing AT thomasschimmang gaiproteinsareindispensableforhearing AT ulrikezimmermann gaiproteinsareindispensableforhearing AT klauspfeffer gaiproteinsareindispensableforhearing AT lutzbirnbaumer gaiproteinsareindispensableforhearing AT andrewforge gaiproteinsareindispensableforhearing AT mireillemontcouquiol gaiproteinsareindispensableforhearing AT marliesknipper gaiproteinsareindispensableforhearing AT berndnurnberg gaiproteinsareindispensableforhearing AT lukasruttiger gaiproteinsareindispensableforhearing |