@article{ae3f4ef20e2e4eb0afe4065e2e11efc7,
title = "ELMOD1 stimulates ARF6-GTP hydrolysis to stabilize apical structures in developing vestibular hair cells",
abstract = "Sensory hair cells require control of physical properties of their apical plasma membranes for normal development and function. Members of the ADP-ribosylation factor (ARF) small GTPase family regulate membrane trafficking and cytoskeletal assembly in many cells. We identified ELMO domain-containing protein 1 (ELMOD1), a guanine nucleoside triphosphatase activating protein (GAP) for ARF6, as the most highly enriched ARF regulator in hair cells. To characterize ELMOD1 control of trafficking, we analyzed mice of both sexes from a strain lacking functional ELMOD1 [roundabout (rda)]. In rda/rda mice, cuticular plates of utricle hair cells initially formed normally, then degenerated after postnatal day 5; large numbers of vesicles invaded the compromised cuticular plate. Hair bundles initially developed normally, but the cell{\textquoteright}s apical membrane lifted away from the cuticular plate, and stereocilia elongated and fused. Membrane trafficking in type I hair cells, measured by FM1-43 dye labeling, was altered in rda/rda mice. Consistent with the proposed GAP role for ELMOD1, the ARF6 GTP/GDP ratio was significantly elevated in rda/rda utricles compared with controls, and the level of ARF6-GTP was correlated with the severity of the rda/rda phenotype. These results suggest that conversion of ARF6 to its GDP-bound form is necessary for final stabilization of the hair bundle.",
keywords = "ARF, Hair cells, Stereocilia",
author = "Krey, {Jocelyn F.} and Dumont, {Rachel A.} and Wilmarth, {Philip A.} and David, {Larry L.} and Johnson, {Kenneth R.} and Barr-Gillespie, {Peter G.}",
note = "Funding Information: This work was supported by NIH Grants R01 DC002368, R01 DC011034, and P30 DC005983 to P.G.B.-G.; the following core facilities: mass spectrometry from the OHSU Proteomics Shared Resource (partial support from NIH core Grant P30 EY010572), confocal microscopy from the OHSU Advanced Light Microscopy Core at The Jungers Center (P30 NS061800 provided support for imaging); and hybridoma cells for JLA20 (deposited by J. J.-C. Lin) and DSHB-GFP-4C9 were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA. We thank David Corey for sharing transcriptomics data before publication. The authors declare no competing financial interests. Funding Information: This work was supported by NIH Grants R01 DC002368, R01 DC011034, and P30 DC005983 to P.G.B.-G.; the following core facilities: mass spectrometry from the OHSU Proteomics Shared Resource (partial support from NIH core Grant P30 EY010572), confocal microscopy from the OHSU Advanced Light Microscopy Core at The Jungers Center (P30 NS061800 provided support for imaging); and hybridoma cells for JLA20 (deposited by J. J.-C. Lin) and DSHB-GFP-4C9 were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA. We thank David Corey for sharing transcriptomics data before publication. Publisher Copyright: {\textcopyright} 2018 the authors.",
year = "2018",
month = jan,
day = "24",
doi = "10.1523/JNEUROSCI.2658-17.2017",
language = "English (US)",
volume = "38",
pages = "843--857",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "4",
}