Mutations of the Mouse ELMO Domain Containing 1 Gene (Elmod1) Link Small GTPase Signaling to Actin Cytoskeleton Dynamics in Hair Cell Stereocilia

Kenneth R Johnson,Chantal M Longo-Guess,Leona H Gagnon,Yoshiro Ishimaru

doi:10.1371/journal.pone.0036074

Abstract

Stereocilia, the modified microvilli projecting from the apical surfaces of the sensory hair cells of the inner ear, are essential to the mechanoelectrical transduction process underlying hearing and balance. The actin-filled stereocilia on each hair cell are tethered together by fibrous links to form a highly patterned hair bundle. Although many structural components of hair bundles have been identified, little is known about the signaling mechanisms that regulate their development, morphology, and maintenance. Here, we describe two naturally occurring, allelic mutations that result in hearing and balance deficits in mice, named roundabout (rda) and roundabout-2J (rda2J). Positional cloning identified both as mutations of the mouse ELMO domain containing 1 gene (Elmod1), a poorly characterized gene with no previously reported mutant phenotypes. The rda mutation is a 138 kb deletion that includes exons 1–5 of Elmod1, and rda2J is an intragenic duplication of exons 3–8 of Elmod1. The deafness associated with these mutations is caused by cochlear hair cell dysfunction, as indicated by conspicuous elongations and fusions of inner hair cell stereocilia and progressive degeneration of outer hair cell stereocilia. Mammalian ELMO-family proteins are known to be involved in complexes that activate small GTPases to regulate the actin cytoskeleton during phagocytosis and cell migration. ELMOD1 and ELMOD2 recently were shown to function as GTPase-activating proteins (GAPs) for the Arf family of small G proteins. Our finding connecting ELMOD1 deficiencies with stereocilia dysmorphologies thus establishes a link between the Ras superfamily of small regulatory GTPases and the actin cytoskeleton dynamics of hair cell stereocilia.

Highlights

Many medically important hearing and balance disorders are caused by defects in the sensory hair cells of the inner ear
Because the Tnfaip813 gene, as well as ELMO domain containing 1 gene (Elmod1), was deleted by the rda mutation, we examined DNA from roundabout-2 Jackson (rda2J) mutant mice for possible alterations of Tnfaip813, the spontaneous occurrence and coisogenic nature of the rda2J mutation would argue against any additional gene mutations
Wildtype ELMOD1 protein is absent in rda2J/rda2J mice, a larger mutant form of the ELMOD1 protein is produced; the extensive duplication of 202 amino acids in the mutant protein likely makes it nonfunctional

Summary

Introduction

Many medically important hearing and balance disorders are caused by defects in the sensory hair cells of the inner ear. Modified microvilli called stereocilia project from the apical surfaces of hair cells and are tethered together by fibrous links to form hair bundles. Hair bundles are essential to the mechanoelectrical transduction process, and proper development and maintenance of these key structures is critical for normal hearing and balance. In addition to the cytoskeletal proteins associated with its actin core, stereocilia contain motor proteins, scaffolding proteins, adhesion proteins, integral membrane proteins, calcium regulatory proteins, and proteins involved in ATP synthesis. Protein complexes forming stereociliary links are important in the development and cohesion of the hair bundle [6,7]

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