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Curr Biol. 2019 Mar 18;29(6):921-934.e4. doi: 10.1016/j.cub.2019.01.051. Epub 2019 Feb 28.

GPSM2-GNAI Specifies the Tallest Stereocilia and Defines Hair Bundle Row Identity.

Author information

1
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
2
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA.
3
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA; Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA; Division of Otolaryngology, Department of Surgery, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
4
The Jackson Laboratory, Bar Harbor, ME 04609, USA; Department of Medicine, Tufts University, Boston, MA 02111, USA; Graduate School of Biomedical Science and Engineering (GSBSE), University of Maine, Orono, ME 04469, USA. Electronic address: basile.tarchini@jax.org.

Abstract

The transduction compartment of inner ear hair cells, the hair bundle, is composed of stereocilia rows of graded height, a property essential for sensory function that remains poorly understood at the molecular level. We previously showed that GPSM2-GNAI is enriched at stereocilia distal tips and required for their postnatal elongation and bundle morphogenesis-two characteristics shared with MYO15A (short isoform), WHRN, and EPS8 proteins. Here we first performed a comprehensive genetic analysis of the mouse auditory epithelium to show that GPSM2, GNAI, MYO15A, and WHRN operate in series within the same pathway. To understand how these functionally disparate proteins act as an obligate complex, we then systematically analyzed their distribution in normal and mutant bundles over time. We discovered that WHRN-GPSM2-GNAI is an extra module recruited by and added to a pre-existing MYO15A-EPS8 stereocilia tip complex. This extended complex is only present in the first, tallest row, and is required to stabilize larger amounts of MYO15A-EPS8 than in shorter rows, which at tips harbor only MYO15A-EPS8. In the absence of GPSM2 or GNAI function, including in the epistatic Myo15a and Whrn mutants, bundles retain an embryonic-like organization that coincides with generic stereocilia at the molecular level. We propose that GPSM2-GNAI confers on the first row its unique tallest identity and participates in generating differential row identity across the hair bundle.

KEYWORDS:

EPS8; GNAI; GPSM2; MYO15A; WHRN; hair bundle; hair cell; staircase-like organization; stereocilia

PMID:
30827920
PMCID:
PMC6516530
[Available on 2020-03-18]
DOI:
10.1016/j.cub.2019.01.051

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