Mutations of the mouse ELMO domain containing 1 gene (Elmod1) link small GTPase signaling to actin cytoskeleton dynamics in hair cell stereocilia

PLoS One. 2012;7(4):e36074. doi: 10.1371/journal.pone.0036074. Epub 2012 Apr 27.

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 (rda(2J)). 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 rda(2J) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / ultrastructure
  • Alleles
  • Animals
  • Cochlea / pathology
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • Deafness / genetics
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Auditory / pathology
  • Hair Cells, Auditory / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation / genetics*
  • Phenotype
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Immunologic / genetics
  • Signal Transduction / genetics*
  • Stereocilia / metabolism*
  • Stereocilia / ultrastructure

Substances

  • Cytoskeletal Proteins
  • Elmod1 protein, mouse
  • GTPase-Activating Proteins
  • RNA, Messenger
  • Receptors, Immunologic
  • Robo2 protein, mouse
  • Monomeric GTP-Binding Proteins